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CORD-19:cb16d307afaecebd683e6d74c8b501ed54b0c9a4 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-51 Sentence denotes Pyrazolone structural motif in medicinal chemistry:
T2 52-75 Sentence denotes Retrospect and prospect
T3 77-85 Sentence denotes Abstract
T4 86-190 Sentence denotes The pyrazolone structural motif is a critical element of drugs aimed at different biological end-points.
T5 191-415 Sentence denotes Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on.
T6 416-600 Sentence denotes Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets.
T7 601-785 Sentence denotes In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.
T8 787-979 Sentence denotes Pyrazolones delegate a cluster of compounds with the nucleus of 1H-pyrazol-3-ol and pyrazolin-5-one ( Fig. 1 ) which have been investigated because of their multiple features and applications.
T9 980-1137 Sentence denotes Since 1883, the synthesis of antipyrine (1) by Knorr, numerous attention has caused by the analgesic and antipyretic activities of pyrazolone analogues [1] .
T10 1138-1298 Sentence denotes The discovery of these features encouraged the researches to synthesize other pyrazolone derivatives with similar behavior but with a better therapeutic action.
T11 1299-2103 Sentence denotes Nowadays, multiple FDA approved drugs containing pyrazolone nucleus have been explored (Fig. 2) , for instances, edaravone (2) has been used as free radical scavenger for the treatment of amyotrophic lateral sclerosis (ALS) [2] , aminophenazone (3) with antipyretic and anti-inflammatory activities has been used in breath tests to measure the cytochrome P-450 metabolic activity in liver function evaluations [3] , eltrombopag (4) has been used for the treatment of low blood platelet counts in adults with idiopathic chronic immune thrombocytopenia [4] , dichloralphenazone (5) has been used for the relief of tension and vascular headaches [5] , metamizole (6) has been used for perioperative pain, cancer pain, acute injury and other forms of pain and is considered as the strongest antipyretic [6] .
T12 2104-2283 Sentence denotes Several investigational small molecules containing pyrazolone have been regarded as drug candidates including sulfamazone (7) [7] , propyphenazone (8) [8] and nifenazone (9) [9] .
T13 2284-2435 Sentence denotes Regarding pyrazolone derivatives, it is important to underline the enormous diversity of classes of synthetic pyrazolone published in existing studies.
T14 2436-2726 Sentence denotes As for the pharmacology investigators, this review is a concise and critical account focusing on the properties of pyrazolones as antimicrobial, antitumor, CNS effect, antiinflammatory, antioxidant, anti-tubercular, antiviral, lipidlowering, antihyperglycemic agents and protein inhibitors.
T15 2727-2806 Sentence denotes We summarized advances of pyrazolone derivatives as well as their SAR (10e189).
T16 2807-3034 Sentence denotes Currently, the existing reviews [10, 11] about pyrazolone derivatives are mainly concerning their catalytic asymmetric synthesis or coordination, the comprehensive review of the bioactivity and the SAR studies are still vacant.
T17 3035-3429 Sentence denotes This review is in order to fill gaps of systematic summarization of biological activities and SAR that could be beneficial for researchers to design novel pyrazolone derivatives, in addition, docking analysis is used to explain interactions between some typical pyrazolone derivatives and potential targets to give a visual appreciation of the roles of pyrazolone group play in the bioactivity.
T18 3430-3521 Sentence denotes Recent advances in the synthesis of pyrazolones have been reported in the literature [12] .
T19 3522-3805 Sentence denotes Condensation of hydrazines with bketoester compounds is the classical method for the synthesis of pyrazolones (Scheme 1), the catalytic conditions are usually the use of organic base like piperidine or inorganic base like NaH in the system of the boiling ethanol or methanol solvent.
T20 3806-4006 Sentence denotes The nucleus of pyrazolones has been widely used to ulteriorly synthesize broad range of derivatives including spiroheterocycles and acylation productions [13] , which features multiple reactive sites.
T21 4007-4199 Sentence denotes The electrophilic substitution at the C-4 position of pyrazolones is an effective synthetic route for the construction of pyrazolones linked with chiral groups and 4-disubstituted pyrazolones.
T22 4200-4338 Sentence denotes In addition, as an important synthon, a, b-unsaturated pyrazolones (R 1 : C]C-R`/ C]N-R`/C]O) can be transformed into diverse pyrazolones.
T23 4339-4457 Sentence denotes When R 1 is C]C-R 0 , they can undergo 1,4-Michael addition as acceptors to generate 4-substituted pyrazole analogues.
T24 4458-4729 Sentence denotes The broad-spectrum of pharmacology properties about pyrazolone derivatives have been reported including antimicrobial, antitumor, CNS activity, anti-inflammatory, antioxidant, antitubercular, antiviral, lipid-lowering, antihyperglycemic and protein inhibitory activities.
T25 4730-4866 Sentence denotes Pyrazolone derivatives have been reported to show the significant antimicrobial activities against multiple types of bacteria and fungi.
T26 4867-5072 Sentence denotes Generally, the antibacterial effect of pyrazolones is better than its antifungal effect, and the inhibitory activity on Gram positive (Gram þve ) and Gram negative (Gram Àve ) strains was distinct as well.
T27 5073-5198 Sentence denotes The bacterial cell membrane is generated with a dense wall comprising several peptidoglycan and teichoic acid layers [14e17].
T28 5199-5424 Sentence denotes In Gram þve bacteria, the adsorption of the biocidal molecules is occurred on the lipoteichoic acid layer which is characterized by the charged nature and the ability to interact with the heteroatoms in the biocide molecules.
T29 5425-5512 Sentence denotes While in the Gram Àve bacteria, the lipid layer is the target of the biocide molecules.
T30 5513-5679 Sentence denotes The drug resistance of traditional antibiotics has aroused people's anxiety about superbacteria, and the attentions giving pyrazolones will pay a light in this field.
T31 5681-5690 Sentence denotes Nasser S.
T32 5691-5693 Sentence denotes A.
T33 5694-5696 Sentence denotes M.
T34 5697-6024 Sentence denotes Khalil [18] described Schiff base compound 10 and its acetyl glucoside derivative 11 (Fig. 3 ) which exhibited the most potent inhibitory effect against the strains of Penicillium italicum, Syncephalastrum racemosum, Aspergillus fumigatus, Bacillus subtilis, Staphylococcus aureus and Escherichia coli at the dose of 400 mg/mL.
T35 6025-6226 Sentence denotes SAR could be deduced that the analogues with nonsubstituted on ring A exhibited the strongest activity and the acetyl glucoside group was more helpful to promote the inhibitory effect than N-glucoside.
T36 6227-6459 Sentence denotes It was notable that the possible intramolecular H-bonding formed by the carbonyl group and the NH moiety improved the inhibition and the triad of permeability, solubility, and potency of the analogues were changed accordingly [19] .
T37 6460-6625 Sentence denotes In 2007, Padmavathi and colleagues [20] synthesized multiple amino-pyrazolone, amino-isoxazolone and amino-pyrimidinone analogues, and evaluated their bioactivities.
T38 6626-6750 Sentence denotes Thereinto, the amino-pyrazolone derivatives 12 and 13 (Fig. 3) showed the most pronounced antimicrobial activity (Table 1 ).
T39 6751-6975 Sentence denotes SAR study elucidated that analogues with amino-hydroxypyrimidinone and N, N-dimethyliminopyrimidinedione showed weak inhibitory effect when compared with analogues modified with amino-pyrazolone and amino-isoxazolone groups.
T40 6976-7076 Sentence denotes Additionally, benzyl sulfonyl analogues exhibited strongest inhibitory effect among the productions.
T41 7077-7224 Sentence denotes Aly and co-workers [21] synthesized antipyrine derivatives 14, 15, 16 and 17 (Fig. 3 ) which were regarded as the prospective inhibitor (Table 1 ).
T42 7225-7451 Sentence denotes SAR investigation expatiated that the presence of pyrazole and the introducing of effective moieties including eCOCH 3 , eCH 3 , -Cl and thiophene group on the scaffold of 4aminoantipyrine showed significant inhibitory effect.
T43 7452-7814 Sentence denotes Hamama and teammates [22] described the antibacterial activity of several pyrazolone analogues, among which compound 18 ( Fig. 3 ) was the most hopeful candidate against E. coli and B. subtilis with the inhibition zoom diameter values of 40 and 36 mm respectively at the concentration of 100 ppm, which was approximately twofold to the reference drug ampicillin.
T44 7815-7946 Sentence denotes The initiatory SAR can be considered as the introduction of piperidine group which was helpful to improve the antibacterial effect.
T45 7947-8112 Sentence denotes Active antimicrobial compounds 19 and 20 produced by Rasapalli et al. [23] (Fig. 3 ) exhibited noticeable antibiofilm activity towards S. aureus strains ( Table 2) .
T46 8113-8192 Sentence denotes Compound 19 suppressed biofilm formation of Staphylococcus epidermidis as well.
T47 8193-8477 Sentence denotes SAR study suggested that the antibacterial scaffold can be acquired by condensation of the carbonyl compounds with the active methylene group on pyrazolone, and the 4-Cl and 2-Br substituted groups on A ring were proved to be the potential active modification for further development.
T48 8478-8746 Sentence denotes Gadhave and colleagues [24] synthesized multi-fluorinated pyrazole-pyrazolone and chromone-pyrazolone compounds 21, 22, 23 and 24 ( Fig. 3 ) which exerted favorable antibacterial effects (Table 1) , whereas all the compounds exhibited poor antifungal activity profile.
T49 8747-8926 Sentence denotes Regarding SAR, it can be speculated as that multifluorinated substitution was contributive to antibacterial while further modification was needed to improve the antifungal effect.
T50 8927-9071 Sentence denotes Narayana Rao et al. [25] designed and synthesized several pyrazolone analogues 25, 26, 27 and 28 ( Fig. 3 ) with favorable activity ( Table 1) .
T51 9072-9327 Sentence denotes As for SAR, the authors disclosed that the amino group on the A ring of pyrazolone markedly elevated the inhibitory effect compared with methyl, and the antimicrobial sequence of R group on the p-position of phenylhydrazine can be generally summarized as:
T52 9328-9354 Sentence denotes Cl > Br > OMe > OC 2 H 5 .
T53 9355-9636 Sentence denotes In 2017, Abdel Reheim and Baker [26] synthesized multiple pyrazolone derivatives and screened the antimicrobial activity, among which compound 29 exhibited strongest antibacterial and antifungal activities, and compound 30 (Fig. 3 ) showed significant antifungal effect (Table 1 ).
T54 9637-9865 Sentence denotes The results of antimicrobial test can be concluded as that the introduction of active substitutions such as pyrano, pyridazine and pyrimidine can promote the antimicrobial activity of the pyrazolone nucleus to different degrees.
T55 9866-9982 Sentence denotes Alkhaldi et al. [27] synthesized pyrazolone derivative 31 ( Fig. 3 ) with multiple antimicrobial effects (Table 1) .
T56 9983-10474 Sentence denotes Concerning SAR, meta dichloro phenyl group on the benzene ring of the Schiff base was helpful to improve the antibacterial activity, and the subsequent molecular docking of the interactions of 31 within potential target glucosamine-6-phosphate synthase (Fig. 4) provided evidence for the antimicrobial effect of 31, the pyrazolone and the 2,4-dichlorophenyl moieties made the different binding models between 31 and glucosamine 6-phosphate, but the inhibitory potency is significant as well.
T57 10475-10826 Sentence denotes Bhattacharjee and colleagues [28] presented pyrazolone compounds 32, 33, 34 and 35 (Fig. 3 ) which exhibited favorable inhibitory effect against Bacillus cereus with the MIC values of 0.78, 0.78, 0.78 and 0.39 mg/mL, respectively, and suppressed the growth of Klebsiella pneumoniae with the MIC values of 0.78, 0.39, 0.39 and 0.78 mg/mL, respectively.
T58 10827-11029 Sentence denotes The preliminary SAR extracted from the results was that pyrazolone group was necessary to the antibacterial activity and the 3,4-dimethoxyl group on A ring was the potential effective substituent group.
T59 11030-11228 Sentence denotes Another research reported that pyrazolone derivatives 36, 37 and 38 (Fig. 3) were potent compounds with anti-bacterial activity and anti-fungal activity exerted to different degree (Table 3 ) [29] .
T60 11229-11477 Sentence denotes In regard to SAR, it was obvious that only compounds 36, 37 and 38 exhibited anti-fungal activity among the analogues, and in the antibacterial evaluation, 36, 37 and 38 were efficient inhibitor of S. mutans, S. typhi and B. subtilis, respectively.
T61 11478-11593 Sentence denotes The 4-Br, 3-F-4-Br and 2,4-dinitro groups on the A ring were the potential active groups for further investigation.
T62 11594-11732 Sentence denotes Sayed et al. [30] synthesized active pyrazolone/pyrazole derivatives 39 and 40 ( Fig. 3) with antimicrobial activity explored in Table 3 .
T63 11733-11917 Sentence denotes With regard to SAR, compared with the inactive pyrazolone derivative which was non-substituted on the benzene ring, compound 39 exhibited moderate activity in the inhibition zone test.
T64 11918-12062 Sentence denotes The pyrazole derivative 40 displayed the strongest inhibitory effect, indicating the potential modification method in the further investigation.
T65 12063-12249 Sentence denotes The author held the point that the antimicrobial effect of the analogues seemed like their trend in the discrepancy in the polarity and the interaction of analogues by cellular membrane.
T66 12250-12402 Sentence denotes Inspired from the structure of cholesterol, compounds 41, 42 and 43 (Fig. 3) were synthesized and investigated for their antimicrobial activities [31] .
T67 12403-12440 Sentence denotes As shown in Table 1 (Table 1 ) [32] .
T68 12441-12606 Sentence denotes SAR indicated that derivatives with pyrazole-1-carbothiohydrazide moiety exhibited higher inhibitory effect than derivatives containing pyrazolyl thiadiazine moiety.
T69 12607-12834 Sentence denotes Additionally, the presence of free carbothiohydrazide unit enhanced the activity of compounds 44, 45 and 46 and the presence of electron-donating groups (EDGs) at the aromatic ring promoted the inhibitory effect of compound 44.
T70 12835-13091 Sentence denotes Bihani and co-workers [33] synthesized zwitterionic pyrazolone analogues 47, 48, 49 and 50 ( Fig. 3) with the antimicrobial properties listed in Table 1 , the moderate inhibitory effects against Pseudomonas syringae and Proteus vulgaris were also reported.
T71 13092-13219 Sentence denotes SAR can be inferred that electrophilic substituted groups on the C-3 or C-4 side of benzene ring could strengthen the activity.
T72 13220-13351 Sentence denotes Oraby and teammates [34] synthesized 2,4-disubstituted phenylhydrazonopyrazolone and isoxazolone analogues as antibacterial agents.
T73 13352-13541 Sentence denotes The results of antibacterial test suggested that the compounds contain the scaffold of pyrazolone like 51 and 52 ( Fig. 3 ) exhibited weak antibacterial effect against the multiple strains.
T74 13542-13664 Sentence denotes Interestingly, the inhibitory activity was promoted simultaneously when the pyrazolone moiety was replaced to isoxazolone.
T75 13665-13955 Sentence denotes Furthermore, docking study indicated that cation-p interactions between isoxazolone analogues and Arg 225, which was a residue played a crucial role in the stabilization of the cofactor during the catalysis in flavin adenine dinucleotide, increased the antibacterial effect of isoxazolones.
T76 13956-14252 Sentence denotes The antibacterial effect of the analogues was influenced by the substitution on C-2 of the phenyl ring, the substitutions with electron withdrawing groups (EWGs) including F and Cl atoms selectivity increased the antibacterial effect against S. aureus compared to bulky moieties such like methyl.
T77 14253-14361 Sentence denotes Microorganisms acquire metals from the environment and use them for many essential cellular processes [35] .
T78 14362-14608 Sentence denotes Metals are able to affect bacterial growth, vitality, and survival [36] , and effectively removing metals using metal chelators makes bacterial cells more susceptible to a variety of antibacterial agents, causing cell lysis and loss of viability.
T79 14609-14768 Sentence denotes Chelators, including EDTA (ethylenediaminetetraacetic acid) and metal complexes of chalcone and flavonoids [37, 38] , have attracting attentions in this field.
T80 14769-14907 Sentence denotes Recently, many research groups made unremitting efforts to the synthesis and characterization of transition metal chelates of pyrazolones.
T81 14908-15033 Sentence denotes Pyrazolones were likely to form several types of coordination compounds due to the several electron-rich donor centers [39] .
T82 15034-15154 Sentence denotes Coordination compounds containing pyrazolone-based ligands are reported to be superior reagents in antimicrobial agents.
T83 15155-15663 Sentence denotes In 2011, a research about Mn(III) mixed-ligand complexes with bis-pyrazolones and ciprofloxacin drug was published [40] , the antimicrobial outcome showed that when added into the strains of microorganisms (E. coli, Serratia marcescens, S. aureus and B. subtilis), the mixed-ligand complexes which contain the moiety of bis-pyrazolones and ciprofloxacin exhibited stronger inhibitory effect compared with bis-pyrazolones, in which compounds 53 and 54 ( Fig. 5) were the potential active antimicrobial agents.
T84 15664-15887 Sentence denotes SAR can be suspected as that the chelation decreased the polarity of the central atom due to partial sharing of its positive charge with the donor moieties and possible electron delocalization over the whole chelation ring.
T85 15888-16082 Sentence denotes The complex molecule promoted the hydrophobic character of the metal chelate and the liposolubility, hence favoring its permeation through the lipoid layer of the cell membrane of microorganism.
T86 16083-16187 Sentence denotes Jadeja and co-workers [41] synthesized multiple pyrazolonebased complexes and evaluated the bioactivity.
T87 16188-16441 Sentence denotes The consequence indicated that compound 55 (Fig. 5) showed stronger inhibitory effect against B. subtilis than other derivatives, at the dose of 3 mM, compound 55 suppressed the growth of B. subtilis strain with the diameter of inhibition zone of 25 mm.
T88 16442-16607 Sentence denotes Schiff bases derivatives of pyrazolone intrigue attention of coordination chemists as versatile spacers due to their viable accessibilities and structural diversity.
T89 16608-16782 Sentence denotes Joseph et al. [42] prepared two kinds of copper complexes derived from 4-formylpyrazolone (56 and 57, Fig. 5 ) and tested the antimicrobial activity against multiple strains.
T90 16783-16962 Sentence denotes The result showed that both compounds 56 and 57 suppressed the growth of stains and the effect were quite comparable to the standard drugs including Levofloxacin and Moxifloxacin.
T91 16963-17041 Sentence denotes 2,4dimethyl derivative 56 was more effective than 3,4-difluorol derivative 57.
T92 17042-17181 Sentence denotes Lunagariya et al. [43] synthesized several organometallic platinum (II) analogues containing pyrazolone and determined their bioactivities.
T93 17182-17342 Sentence denotes Among the analogues, compound 58 ( Nair and co-workers [44] prepared some metal complexes with derived from pyrazolone and evaluated their antimicrobial potent.
T94 17343-17596 Sentence denotes The synthetic analogues exhibited antimicrobial effects to different degrees, among which compound 59 (Fig. 5 ) was the most promising one with the highest zones of inhibition i.e. 10.5, 14.3 and 11.2 mm measured in P. aeruginosa, S. aureus and E. coli.
T95 17597-17759 Sentence denotes SAR research suggested that the metal chelates were more toxic than the parent ligands against the same microorganism and under identical experimental conditions.
T96 17760-17843 Sentence denotes The biological activity of complexes followed the order of the change of metal ion:
T97 17844-17903 Sentence denotes Ni (II) > Co (II) > Zn (II) > Cu (II) > Schiff base ligand.
T98 17904-18101 Sentence denotes In the 21st century, malignant tumor is one of the leading causes of death and developing new antitumor agents with less drug resistance and side effects needs to be done as soon as possible [45] .
T99 18102-18311 Sentence denotes In recent years, pyrazolone derivatives and their metal complexes have attracted the great attention of researchers for their potential antitumor activity and their less drug resistance and side effects [46] .
T100 18312-18391 Sentence denotes So far, diverse pyrazolone analogues with antitumor potency have been reported.
T101 18392-18527 Sentence denotes Factor Receptor 2 (VEGFR-2), also known as Flk-1, is mainly expressed in vascular endothelial cells and hematopoietic stem cells [47] .
T102 18528-18668 Sentence denotes It is highly expressed in a variety of malignant tumors and plays a significant regulatory role in the metastasis and angiogenesis of tumor.
T103 18669-18787 Sentence denotes Taking VEGFR-2 as the target, the search for VEGFR-2 inhibitors provides a good way to find some new anticancer drugs.
T104 18788-19003 Sentence denotes Based on conserved active binding sites of VEGFR-2 and similar interaction conformation with ligands, several novel inhibitors of VEGFR-2 have been developed [48] , in which pyrazolones play important roles as well.
T105 19004-19292 Sentence denotes In 2006, Tripathy and co-workers [49] synthesized a train of heterocyclic-substituted pyrazolones and tested inhibitory potency against VEGFR-2 kinase, among which compound 60 ( Fig. 6 ) was proved to be the most potential derivative inhibiting VEGFR2 kinase with the IC 50 value of 6 nM.
T106 19293-19466 Sentence denotes SAR for the analogues can be summarized that replacement on the indole ring exhibited further potency increase against VEGFR-2 especially at the position of C-4 on the ring.
T107 19467-19630 Sentence denotes Inspired from existing VEGFR-2 inhibitors, the same research group [50] modified the structure 61 by introducing a 4-benzyloxy substituent to generate compound 62.
T108 19631-19820 Sentence denotes Further investigation on structural modifications of the aromatic moiety of 62 revealed that compound 63 (Fig. 6 ) was the most promising anaplastic lymphoma kinase (ALK) inhibitor (IC 50 :
T109 19821-19827 Sentence denotes 5 nM).
T110 19828-19965 Sentence denotes As for SAR, it was demonstrated that a plenty of halogen substituent groups on the aromatic ring were favored for ALK inhibitory potency.
T111 19966-20140 Sentence denotes Moreover, the authors paid attention to the modification of the heterocyclic moiety and SAR analysis was concluded that compound bearing thiazole increased inhibition of ALK.
T112 20141-20301 Sentence denotes Gu et al. [51] prepared a series of novel pyridine analogues bearing pyrazolone skeleton and evaluated the cell proliferation activities of synthetic analogues.
T113 20302-20410 Sentence denotes Among all compounds, 64, 65 and 66 ( Fig. 6 ) exhibited favorable inhibitory potential on c-Met and VEGFR-2.
T114 20411-20492 Sentence denotes The most promising analogue 66 significantly inhibited the targets c-Met (IC 50 :
T115 20493-20522 Sentence denotes 0.11 mM) and VEGFR-2 (IC 50 :
T116 20523-20549 Sentence denotes 0.19 mM) kinases in vitro.
T117 20550-20706 Sentence denotes SAR analyses suggested that substitution of pyridine amine moiety with longer polar side chains or with hydrophilic group could improve inhibitory activity.
T118 20708-20913 Sentence denotes Receptor tyrosine kinase c-mesenchymal epithelial transition factor (c-Met), a vital target in antitumor therapy, plays a crucial role in the occurrence, development, metastasis and angiogenesis of tumors.
T119 20914-21168 Sentence denotes In 2012, according to the theory of Structure-Based Drug Design, Norman and co-workers [52] designed and synthesized a series of class II c-Met inhibitors, among which derivative 67 ( Fig. 6 ) was confirmed to possess excellent potency against c-Met (Ki:
T120 21169-21177 Sentence denotes 1.0 nM).
T121 21178-21272 Sentence denotes This privilege compound was demonstrated to show binding affinity not only with c-Met (PDB ID:
T122 21273-21328 Sentence denotes 3U6H) (Fig. 7A ), but also with VEGFR-2 kinase (PDB ID:
T123 21329-21393 Sentence denotes 3U6J) ( Fig. 7B ) with the help of X-ray analysis of cocrystals.
T124 21394-21670 Sentence denotes Obviously, the pyrazolone moiety plays crucial roles in occupying active sites of binding pocket, forming the pi-alkyl with Val 1155 in c-Met and H-bond with Asp 1046 in VEGFR-2 kinase, suggesting the broad prospect of pyrazolones developing as antitumor agents in the future.
T125 21671-21745 Sentence denotes This study provides a new strategy for designing more selective analogues.
T126 21746-21907 Sentence denotes Therefore, Liu et al. [53] synthesized a cluster of pyrazolone-based analogues according to compound 67 and screened the most selective class II c-Met inhibitor.
T127 21908-21988 Sentence denotes Among them, compound 68 (Fig. 6 ) was the representative active antitumor agent.
T128 21989-22191 Sentence denotes SAR investigation revealed that the 6-methoxy group of quinoline in the region (A), the pyridine in the central ring (B) and 2-hydroxypropyl side chain at N-1 could promote the selectivity and activity.
T129 22192-22293 Sentence denotes In addition, the polar functionality at C-5 position of the pyrazolone was important for selectivity.
T130 22294-22471 Sentence denotes A potential compound 69 (Fig. 6 ) was designed and synthesized by Zhou and colleagues [54] , inspired from the structure of abozantinib and foretinib as c-Met inhibitor (IC 50 :
T131 22472-22563 Sentence denotes 2.20 nM) to show antiproliferative effect against multiple cancer cell lines, respectively.
T132 22564-22786 Sentence denotes SAR investigation could be concluded that substitution of the cyclopropane-1,1-dicarboxamide framework of foretinib with the N-aryl-pyrazolone-4-imino and 2,4-imidazolinedione group sustained the potent antitumor activity.
T133 22787-22960 Sentence denotes Additionally, analogues with mono/double-EDGs on the ring B were more active, especially eCF 3 at the C-2 position of ring B were more effective than eCH 3 or eOCH 3 groups.
T134 22961-22969 Sentence denotes 3.2.1.3.
T135 22970-23009 Sentence denotes Other antitumor pyrazolone derivatives.
T136 23010-23123 Sentence denotes Human SIRTs (Sirtuins) are relative to cell senescence, apoptosis, metabolism, proliferation and differentiation.
T137 23124-23197 Sentence denotes In the past decade, they have emerged as targets for cancer chemotherapy.
T138 23198-23290 Sentence denotes SIRT1, SIRT2 and SIRT3 are relatively important in the SIRTs family with extensive research.
T139 23291-23402 Sentence denotes Mahajan and teammates [55] prepared a multiple of fivemembered ring pyrazolone analogues as Sirtuin inhibitors.
T140 23403-23552 Sentence denotes Among these products, compounds 70 and 71 (Fig. 6) showed the inhibitory activities against SIRT1 with IC 50 values of 41 mM and 27 mM, respectively.
T141 23553-23647 Sentence denotes In addition, compound 70 displayed the most promising inhibitory effect against SIRT3 (IC 50 :
T142 23648-23654 Sentence denotes 6 mM).
T143 23655-24054 Sentence denotes According to the pharmacophore investigations, SAR can be sum up as the presence of pyrazolone ring was important to improve the inhibitory effect on SIRT1 and SIRT3 through maintaining the balance of H-bond donor and acceptor moieties, from the active analogue 71, the introduction of bulky hydrophobic benzene group at the C-6 position of naphthalene was helpful to increase the activity on SIRT3.
T144 24055-24209 Sentence denotes Moreover, the selective inhibition on SIRT2 was significantly elevated when the H-bond donor NH group on the position 1 was replaced as H-bond acceptor O.
T145 24210-24365 Sentence denotes It's reported that pyrazolone was potential to be the starting point for generating RalA inhibitors, which were often activated in human cancer cell lines.
T146 24366-24494 Sentence denotes Derivative 72 (Fig. 6) , as the most promising anticancer candidate, was designed and synthesized by Zhang and colleagues [56] .
T147 24495-24719 Sentence denotes The consequence for ability of compound 72 inducing apoptotic death in PANC-1 cells showed that derivative 72 suppressed RalA according to inducing the accumulation of ROS and trigger mitochondrial apoptosis in PANC-1 cells.
T148 24720-24890 Sentence denotes Markovic and colleagues [57] designed and synthesized compound 73 and its 5-phenylpyrazole derivative 74 (Fig. 6 ) which exhibited the most promising activity (Table 4 ).
T149 24891-25053 Sentence denotes QSAR study revealed that geometrical and topological are the most momentous factors for effect of the analogues, for instance, the size and shape of the molecule.
T150 25054-25255 Sentence denotes Containing planar benzene group at N-1 position of pyrazolone showed superior inhibitory potency on both cells tested for it was a more favorable conformation moiety when interacting with active sites.
T151 25256-25389 Sentence denotes Herein, the inhibitory effect on the target mostly depended on fragment at the C-4 position through forming Hbonds with active place.
T152 25390-25522 Sentence denotes Pyrazolone derivatives such as 4-aminoantipyrine are well known compound used widely prophylactic of some diseases including cancer.
T153 25523-25695 Sentence denotes Ghorab and colleagues [58] synthesized a variety of pyrazolone derivatives 75e81 (Fig. 6 ) inspired from 4aminoantipyrine and determined the anticancer activity (Table 4) .
T154 25696-25822 Sentence denotes SAR study can be summarized that the most potent compound belonged to the pyrimidine derivatives especially the halogen group.
T155 25823-25959 Sentence denotes Dube and colleagues [59] synthesized a cluster of pyrazolone heterocyclic derivatives and evaluated their cytotoxic activities in vitro.
T156 25960-26100 Sentence denotes The results of brine shrimp lethality assay showed that compound 82 displayed a favorable cytotoxic activity than standard cyclophosphamide.
T157 26101-26308 Sentence denotes In addition, compounds 82 and 83 (Fig. 6 ) were found to be prominent analogues with the lethality concentration (LC 50 ) values being 10.8 mg/mL and 14.5 mg/mL in sulforhodamine B (SRB) assay, respectively.
T158 26309-26510 Sentence denotes SAR investigation implied that the dimethoxy substitution on ring A increased the antitumor activities, the group of hydrophobicity and hydrophilicity played a significant role in cytotoxic activities.
T159 26511-26643 Sentence denotes Gouda et al. [60] prepared several pyrazole analogues and tested the cytotoxicity against the Ehrlich ascites carcinoma cells (EAC).
T160 26644-26725 Sentence denotes To detail, the cytotoxicity data clearly displayed that and compounds (Table 5) .
T161 26726-27111 Sentence denotes SAR can be recapitulated that introducing a hydrazopyrazol-5-one ring in position 2 to benzothiophene was important to the cytotoxic activity, furthermore, the order of antitumor activities of compound follows 86 < 87 < 88 and 84 < 89 < 90 (Fig. 6) , it can be speculated that the group of COOEt at position 3 of the thiophene ring system in compounds increased the antitumor activity.
T162 27112-27312 Sentence denotes In 2013, Vyas and colleagues [61] synthesized the new pyrazolone based complex 91 (Fig. 8) for the first time, which was suggested to be a potent antitumor agent against lung cancer cell lines (A549).
T163 27313-27598 Sentence denotes According to evaluation of the cytotoxic activities against A549 cell lines and noncancerous rat cardiomyocytes (H9C2) cell lines in vitro, the result displayed that compound 92 (Fig. 8) Three kinds of pyrazolone complexes 94e96 (Fig. 8 ) were synthesized by Bakr and co-workers [63] .
T164 27599-27800 Sentence denotes The MTT assay outcomes implied that HL exhibited the better cytotoxic activity against HePG2 and PC3 cell lines than 5-Fluorouracil with IC 50 values being 5.69 and 6.80 mg/mL, respectively (Table 6) .
T165 27801-27877 Sentence denotes For metal complexes, the order of cytotoxicity was found to be 95 > 94 > 96.
T166 27878-28014 Sentence denotes Zhang and colleagues [64] synthesized two new transition metal complexes with 4-acylpyrazolone derivative as potential antitumor agents.
T167 28015-28270 Sentence denotes According to the results of antitumor determination, the complex 97 ( Fig. 8 ) was proved to exhibit higher cytotoxicity activity with IC 50 values being 1.9 mg/mL for human esophageal cancer cells (Eca-109) and 1.2 mg/mL for cervical cancer cells (HeLa).
T168 28271-28349 Sentence denotes The study suggested that the complex 97 might be an effective agent for tumor.
T169 28350-28508 Sentence denotes Because of the intricate pathogenesis and devastating effects, CNS disease is still a challenge for researchers to find novel precursors as the therapy [65] .
T170 28509-28832 Sentence denotes In view of the experiment of the development of edaravone, several pyrazolones have been taken into account to be the CNS agents, existing literatures mainly focus on the anticonvulsant, antidepressant, anti-amyotrophic lateral sclerosis, anti-Alzheimer's activities and inhibitory effect against other CNS related targets.
T171 28833-28985 Sentence denotes Herein, we summarized the bioactivity and SAR for the synthetic derivatives, wishing to give evidence for pyrazolones to develop as CNS clinical agents.
T172 28986-29199 Sentence denotes Epilepsy is a chronic neurological disorder syndrome identified by the spontaneous recurrence of seizures which can disrupt periods of more or less normal electroencephalographic (EEG) activity and behavior [66] .
T173 29200-29398 Sentence denotes Currently the anticonvulsant drugs are chiefly derived from benzodiazepines or GABA (g-aminobutyric acid) analogues, pyrazolone derivatives are likely to provide a novel orientation for drug design.
T174 29399-29566 Sentence denotes Eldebss et al. [67] synthesized pyrazolone-based heterocycle compounds as monoamine oxidase (MAO) inhibitors and evaluated the tryptamine seizure potentiation in rats.
T175 29567-29671 Sentence denotes The results manifested that compounds 97 and 98 ( Fig. 9) were the most promising candidates (Table 7) .
T176 29672-29783 Sentence denotes Viveka et al. [68] prepared pyrazolone analogues 99 and 100 ( Fig. 9) with favorable anticonvulsant activities.
T177 29784-30030 Sentence denotes In the maximal electroshock (MES) test, compound 99 performed the best protective potency with the protection ratio of 79.76% and no significant toxicity was determined at the dosage of 25 mg/kg, while in the analgesic test it showed weak effect.
T178 30031-30103 Sentence denotes Compound 100 exhibited moderate protection on the reaction time of mice.
T179 30104-30202 Sentence denotes SAR study demonstrated that the existing of pyrazolone moiety elevates the anticonvulsant potency.
T180 30203-30393 Sentence denotes As for the analgesic effect di-Cl substituent group on the heterocyclic systems promoted the activity, whereas slightly less activity was determined for the analogues with di-F substituents.
T181 30394-30546 Sentence denotes A cluster of pyrazolone analogues were synthesized and assessed for the anticonvulsant and antidepressant activities by Abdel-Aziz and colleagues [69] .
T182 30547-30884 Sentence denotes Compounds 101, 102 and 103 ( Fig. 9 ) displayed the most potent protective potency against pentylenetetrazole (PTZ)-induced clonic seizures in mice at a dosage level of 20 mg/kg with the protective ratio for 74.5, 78.7 and 74%, respectively, which was close to phenobarbital sodium (30 mg/kg) and better than phenytoin sodium (30 mg/kg).
T183 30885-31233 Sentence denotes Preliminary SAR study can be concluded that the existence of cricoid pyrazolone group increased the anticonvulsant effect compared with the linear chain-hydrazide analogues, and thiophene acyl moiety was the most potent substituted group, while linear chain-hydrazide analogues performed better than pyrazolones in the antidepressant determination.
T184 31234-31355 Sentence denotes Merugumolu and co-workers [70] prepared multiple pyrazolone derivatives and estimated the anti-depressant effect in vivo.
T185 31356-31610 Sentence denotes The consequence demonstrated that the most promising derivatives 104 and 105 (Fig. 9 ) possessed remarkable antidepressant activity in forced swimming test and tail suspension test (Table 8) , with the relative values in the same magnitude of imipramine.
T186 31611-31756 Sentence denotes As for SAR, the substituted groups on the 3,4-position of the ring of aromatic hydrazine exhibited better activity than other substituted groups.
T187 31757-32165 Sentence denotes The pyrazolone skeleton is an effective group characterized in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for amyotrophic lateral sclerosis (ALS), which is an orphan neurodegenerative disease so for without a cure with the incidence of 1e2 per 100000 per year and 2e5 years from diagnosis to death [71, 72] .
T188 32166-32531 Sentence denotes A cluster of pyrazolone analogues were screened and evaluated for the anti-ALS activity from FDA approved drugs and biochemical reagents by Radhia and co-workers [73] , as the most potent skeleton, the arylsulfanyl pyrazolones showed 100% efficacy compared with the positive control, radicicol (80% efficacy) in the test of G93A-SOD1 expression in PC12 cells model.
T189 32532-32722 Sentence denotes CMB-003299 (106, Fig. 9 ) was the typical compound to decrease the mutant SOD1 aggregation with the ED 50 value of 400 nM, and the weak cytotoxic effect was detected with the LD 50 > 100 mM.
T190 32723-32833 Sentence denotes In the sequent research, a series of ether analogues with more metabolically stability were synthesized [74] .
T191 32834-33046 Sentence denotes The most effective derivative 107 (CMB-087229) (Fig. 9) showed superior potency and in vitro pharmacological and pharmacokinetic features including protection against the mutant SOD1-induced cytotoxicity (ED 50 :
T192 33047-33231 Sentence denotes 67 nM), good performance in the evaluation of potassium channel (10 mM), protection of primary cortical neurons, Caco-2 permeability, rat liver microsomes and cytochrome P450 isozymes.
T193 33232-33482 Sentence denotes Moreover, in vivo for its efficacy in an ALS mouse model, pharmacokinetic profile and brain penetration were investigated as well, compound 107 (1.0, 10, and 20 mg/kg) dose-dependently extended the survival of SOD1 G93A mice at the dose of 300 mg/kg.
T194 33483-33568 Sentence denotes In addition, compound 107 exhibited favorable blood-brain barrier penetration effect.
T195 33569-33737 Sentence denotes SAR research revealed that the size and electronics were imperative features at the meta-positions of the derivatives, the potency of analogues reduced in the sequence:
T196 33738-33762 Sentence denotes Cl > CF 3 > F > Br > Ph.
T197 33763-33931 Sentence denotes Based on the structure of leading compound edaravone, Tok and co-workers [75] synthesized a cluster of analogues and investigated the potential anti-Alzheimer activity.
T198 33932-34065 Sentence denotes Among the analogues, compounds 108 and 109 (Fig. 9 ) exerted most potent inhibitory effects, with the detail data listed in Table 9 .
T199 34066-34294 Sentence denotes For the instance of the most potent AChE inhibiting agent 108 and MAO-B inhibiting agent 109, the initial SAR could be summarized as that the variation of substituent groups strongly affected the inhibitory potency of analogues.
T200 34295-34396 Sentence denotes Basic nitrogen atom in substituent groups of 108 significantly promoted the AChE inhibitory activity.
T201 34397-34478 Sentence denotes In addition, incorporation of EWG increased the MAO-B inhibitory activity of 109.
T202 34479-34749 Sentence denotes It can be seen from the docking analysis that compound 108 was prepared with similar size with donepezil (Fig. 10) , and the room of cyclopentanone ring can be occupied by pyrazolone ring, providing the evidence of the activity and the idea to capture Alzheimer disease.
T203 34750-34876 Sentence denotes A major inhibitory neurotransmitter in the mammalian brain is GABA that delivers primarily through the GABA A receptors [76] .
T204 34877-35019 Sentence denotes GABA A receptors are considered to be heteropentameric transmembrane glycoprotein spanning both extracellular and intracellular regions [77] .
T205 35020-35220 Sentence denotes Inspired from the pyrazolone-based precursors 110e112 (Fig. 9 ), Hintermann and co-workers [78] synthesized several analogues as the ligands for the benzodiazepine binding site of the GABA A receptor.
T206 35221-35606 Sentence denotes Among them, compound 113 ( Fig. 9 ) was the typical compound with the affinity of IC 50 values of a1 GABA A receptor, a2 GABA A receptor, a1 GABA A BZ receptor, a2 GABA A BZ receptor for 49, 271, 46 and 271 nM, respectively, however, the weak activity of compound 113 was observed in anxiety models in vivo, which was suspected due to the high level of clearance (in vitro: CL int rat:
T207 35607-35626 Sentence denotes 128.3 mL/min * mg).
T208 35627-35875 Sentence denotes SAR study suggested that the 2-Cl-benzyl substituent group was initially maintained for the purpose to investigate the influence of core modifications, variations of substituent groups on the aromatic pyrazolone moiety leading to the mixed results.
T209 35876-35972 Sentence denotes The corresponding analogues were very weak agonists at a2 and some behaved as antagonists at a1.
T210 35973-36329 Sentence denotes Glycogen synthase kinase 3 (GSK-3), a regulator of glycogen metabolism, has been well known to be involved in a variety of intracellular signaling, and a lot of GSK-3 inhibitors has been used for the treatment of CNS disorders including Alzheimer's disease (AD) [79] , Parkinson's disease [80] , stroke, traumatic brain injury, and bipolar disorders [81] .
T211 36330-36500 Sentence denotes Pyrazolone derivatives were chronicled to show activity on this target as well [82] , the most promising compound 114 (Fig. 9 ) inhibited GSK-3 with IC 50 value of 34 nM.
T212 36501-36714 Sentence denotes Further investigation demonstrated that this compound possessed good kinase selectivity, and protective effects in oxidative stress mode in neuronal cell and locomotor hyperactivity in C57BL/6J mice were observed.
T213 36715-36911 Sentence denotes SAR investigation indicated that nonsubstitution on the A ring was advantageous for the activity because only compound 114 exhibited the pronounced inhibitory effect among the synthetic compounds.
T214 36912-37191 Sentence denotes Interestingly, the known GSK-3 inhibitors i.e. bisindol-maleimides (115) [83] and hymenialdisine (116) [84] (Fig. 9) contain the moieties structurally similar to the pyrazolone scaffold, which indicated the reasonability of using pyrazolone for the design of the GSK-3 inhibitor.
T215 37192-37455 Sentence denotes According to the structure of (S)-a-aminoadipic acid, which was an activating agent of important functional excitatory amino acid receptor mGlu2 and mGlu6 subtypes, compounds 117 and 118 ( Fig. 9) were synthesized by Zimmermann et al. [85] thought some reactions.
T216 37456-37782 Sentence denotes However, no significant agonist or antagonist activity from test compounds at the mGlu 1a , mGlu 2 , mGlu 4a , or mGlu 6 subtypes were observed at the dose of 1 mM, the inappropriate pK a of analogues was considered as the potential reason of obstruct interaction of substituted groups with appropriate sites at the receptors.
T217 37783-37994 Sentence denotes More than 100 years of synthetic work have resulted in three privileged pyrazolones derivatives with anti-inflammatory potency, namely antipyrine, propyphenazone and metamizole which are still widely used [86] .
T218 37995-38163 Sentence denotes The structure characteristic that methyl groups attach to the ring nitrogen atoms to enhance the activity has been retained from antipyrine to newly reported analogues.
T219 38164-38358 Sentence denotes Based on the structure of marketed anti-inflammatory drugs including antipyrine and aminophenazone, several pyrazolone derivatives have been designed and synthesized as anti-inflammatory agents.
T220 38359-38639 Sentence denotes With the thorough understand of inflammatory reactions, using single mice or rat model to evaluate the analgesic effect gradually fall short of demand to investigate the activity, more and more targets are involved into the determination including COX-1, COX-2, 5-LOX, TNF-a, etc.
T221 38640-38961 Sentence denotes Pyrazolones with anti-inflammatory effects tend to inhibited the activities of COXs and LOXs, which catalyze the conversion of arachidonic acid into prostaglandins or leukotrienes, meanwhile, phosphatase inhibitory of pyrazolones have also been disclosed [87] , indicating the potential of pyrazolone motif in this field.
T222 38962-39132 Sentence denotes The structural similarity between pyrazolone and COX-2 selective inhibitor celecoxib also provides possibility to develop them into potential clinical candidates [88e91].
T223 39133-39514 Sentence denotes The gastrointestinal side effects existing in the usage of COX-1 inhibitors and the cardiovascular side effects in COX-2 inhibitors suggest researchers to consider the inhibitory potency of anti-inflammatory agents on both COX-1 and COX-2, the story of the development of imrecoxib and the conception of moderate selectivity for COX-2 enzyme have been reported as references [19] .
T224 39515-39833 Sentence denotes It can be seen from the binding affinity models of celecoxib and pyrazolone derivative 131 with COX-1 and COX-2 ( Fig. 12 ) that pyrazolone group maintain the similar pi-alkyl effect with electron group of alkyl groups in the pocket residues compared to pyrrazole ring because of its property similar to aromatic ring.
T225 39834-40119 Sentence denotes The carbonyl group in pyrrazole is a favorable hydrogen acceptor which is feasible to form potential Hbond with alkaline amino acids like arginine, lysine and histidine, meanwhile, the amino group is a hydrogen donor easy to form hydrogen bond with residues like glutamine (Fig. 12D) .
T226 40120-40337 Sentence denotes A cluster of pyrazolone and amino pyrimidine derivatives 119e124 (Fig. 11) were synthesized by Antre and co-workers [92] , with obvious anti-inflammatory potency in carrageenan-induced rat paw edema model (Table 10 ).
T227 40338-40598 Sentence denotes In regard to SAR, in contrast to the substitution of chlorine and nitro, the anti-inflammatory effects of these analogues were significantly promoted when the electrondonating groups of C-6 aminopyrimidine benzene ring were hydroxyl, methoxy and dimethylamine.
T228 40599-40745 Sentence denotes Nadia and colleagues [93] synthesized multiple pyrazolonepyridazine conjugates and screened their anti-inflammatory activity in vivo and in vitro.
T229 40746-40927 Sentence denotes Compound 125 (Fig. 11 ) exhibited the strongest anti-inflammatory activity in the test of carrageenaninduced mice paw edema model and in COX-1 and COX-2 inhibition test (Table 10) .
T230 40928-41021 Sentence denotes It also inhibited the production of inflammatory cytokines including TNF-a and IL-6 in serum.
T231 41022-41156 Sentence denotes SAR study showed that the replacement with bulky aliphatic secondary amines such as morpholine exerted good anti-inflammatory effects.
T232 41157-41423 Sentence denotes Mannich base derivatives 126 and 127 (0.03 mmol/kg) (Fig. 11 ) displayed the remarkable anti-inflammatory effect on the carrageenan-induced acute albino rats paw edema model with inhibitory rates of 77.88% and 79.91%, respectively, after 6 h of administration [94] .
T233 41424-41583 Sentence denotes The preliminary SAR demonstrated that analogues containing EWGs in the Mannich base phenyl ring at position 4, especially sulfonic group enhanced the activity.
T234 41584-41687 Sentence denotes Abbady and co-workers synthesized some new pyridines, pyrans, and indazoles with pyrazolone ring [95] .
T235 41688-41985 Sentence denotes Among the synthetic products, indazole derivatives 128 and 129 (10 mg/kg) (Fig. 11 ) obviously suppressed swelling of in rat hind paws induced 5 h after injection of carrageenan, with inflammatory inhibition rates of 56.20% and 55.20%, respectively, indicating excellent antiinflammatory activity.
T236 41986-42119 Sentence denotes A series of 5-methyl-2-phenyl-1H-pyrazol-3 (2H)-one analogues were prepared and determined for their anti-inflammatory effects [96] .
T237 42120-42300 Sentence denotes The outcome showed that the derivatives 130 and 131 (Fig. 11 ) were proved to have superior inhibitory potency against both the targets of inflammation COX-1 and COX-2 (Table 10) .
T238 42301-42492 Sentence denotes Furthermore, derivatives 130 and 131 also exhibited favorable antiinflammatory effect in carrageenan induced rats paw edema model with ED 50 values of 102 and 109 mg/kg in vivo, respectively.
T239 42493-42640 Sentence denotes Regarding SAR, pyrazolones containing C-3 methyl group, C-4 urea substitution and carbonyl at 5-position posed an impact on COX enzymes inhibition.
T240 42641-42786 Sentence denotes The substituent with urea-phenyl group at 3phenyl ring was more active than that containing chlorine at the same position and unsubstituted urea.
T241 42787-42891 Sentence denotes Moreover, thiourea derivatives imparted strengthen activity compared with those with urea and guanidine.
T242 42892-43031 Sentence denotes Ashraf et al. [97] successfully prepared two series of pyrazolone analogues and tested their anti-inflammatory effect in vivo and in vitro.
T243 43032-43177 Sentence denotes The derivative 132 and the enolate133 (Fig. 11 ) displayed excellent inhibitory activity on COX-2 (Table 10 ) as well as potent edema inhibition.
T244 43178-43342 Sentence denotes SAR investigation showed that these compounds with unsaturated moiety such as the allyl and aryl groups maintained stronger activities than those with alkyl groups.
T245 43343-43464 Sentence denotes Thiourea analogues 132 also improved anti-inflammatory potency in the presence of the bulky hydrophobic cyclohexyl group.
T246 43465-43598 Sentence denotes El Sayed and colleagues designed and synthesized novel heterocyclic derivatives containing antipyrine and pyrazolone framework [98] .
T247 43599-43784 Sentence denotes The pharmacology tests result revealed that derivatives 134e136 (Fig. 11 ) exhibited significant anti-inflammatory activities in different degree both in vivo and in vitro ( Table 10 ).
T248 43785-44051 Sentence denotes The SAR study indicated that the presence of the 3-benzo[d] [1, 3] dioxole ring system and the N-containing heterocyclic amine attached to the methyl group at 4-position of the antipyrine structure was very essential for activity as in case of compounds 134 and 135.
T249 44052-44197 Sentence denotes A cluster of novel pyrazolone analogues containing aminosulfonyl group were synthesized and investigated for the anti-inflammatory potency [99] .
T250 44198-44455 Sentence denotes The outcome showed that three compounds 137e139 (Fig. 11) , as potent anti-inflammatory agents, exerted strong inhibitory effects against both COX-2 (Table 10) Fahmy et al. [100] tested anti-inflammatory effects of several novel O-substituted salicylamides.
T251 44456-44594 Sentence denotes Among all analogues, pyrazolone derivative 141 (Fig. 11 ) exhibited moderate antiinflammatory activity in carrageenan-induced edema model.
T252 44595-44739 Sentence denotes The multiple bioactivity test results indicated the pyrazolone and the structurally similar group pyrazole could be the potential substitutions.
T253 44740-44883 Sentence denotes Golebiowski and co-workers synthesized some novel monocyclic pyrazolone and investigated their inhibition on the inflammatory cytokines [101] .
T254 44884-45040 Sentence denotes The outcome showed that compound 142 (Fig. 11 ) significantly reduced the expression of TNF-a induced by lipopolysaccharide (LPS) with IC 50 value of 13 nM.
T255 45041-45258 Sentence denotes Furthermore, through SAR study, it can be found that benzyl amino substituents were more active than those of aminopyridine ring, and N-methyl substitution on the pyrazolone was more effective than ethyl substitution.
T256 45259-45377 Sentence denotes Currently, the topic of inflammatory reaction has beyond the analgesic agents, immunoreactivity targets also involved.
T257 45378-45592 Sentence denotes The author observed the interactions of p38 kinase with another potential synthesized pyrazolone derivative 143 (Fig. 13) , in which the piperidine ring was introduced to gain the better pharmacokinetic parameters.
T258 45593-45765 Sentence denotes The carbonyl group of pyrazolone ring was proved to form the H-bond with the amine group of Lys 53, revealing the importance of pyrazolone moiety of this type of inhibitor.
T259 45766-45876 Sentence denotes Free radicals, known to be highly reactive molecules resulted via different biochemical reactions in the body.
T260 45877-46000 Sentence denotes These free radicals lead the other metabolites to be oxidized and caused different diseases due to oxidative stress [102] .
T261 46001-46227 Sentence denotes Pyrazolones played a role in antioxidant activity, referring to the antioxidant mechanism of edaravone, C]C double bond formed by the action of tautomerism of carbonyl group on pyrazolone was considered to be important [103] .
T262 46228-46387 Sentence denotes In the light of the structure motif of 4-aminoantipyrine, Schiff base derivative 144 (Fig. 14) was prepared and determined for the antioxidant activity [104] .
T263 46388-46472 Sentence denotes The derivative 144 exerted a strong antioxidant effect with IC 50 value of 31.26 mM.
T264 46473-46653 Sentence denotes As a non-phenolic antioxidant agent, the antioxidant effect of compound 144 was considered to be relative to the formation of proton free radicals by the C-7 or C-11 methyl groups.
T265 46654-46989 Sentence denotes The Schiff base pyrazolone analogues were also synthesized by Khan et al. [105] , among the products, phenol productions 145e148 (Fig. 14) exhibited significant antioxidant effect in DPPH test with the IC 50 values of 20.14, 19.12, 17.14, 15.16 mM, respectively, which was even stronger than the standard drug n-propyl gallate (IC 50 :
T266 46990-47000 Sentence denotes 30.27 mM).
T267 47001-47213 Sentence denotes SAR study revealed that double phenol group substituted analogues performed better than other moieties because of the reducibility of phenolic hydroxyl group, and 2.5-diOH substitution was stronger than 2,4-diOH.
T268 47214-47434 Sentence denotes Gaffer and co-workers [106] screened the antioxidant activity of a cluster of thiazolyl-pyrazolone derivatives through 2, 2 0 -azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation decolorization assay.
T269 47435-47571 Sentence denotes Compounds 149 and 150 (Fig. 14) (2 mM) exhibited the strongest antioxidant potency with the inhibition of 88.6% and 85.7%, respectively.
T270 47572-47672 Sentence denotes Thereinto, compound 149 exhibited better activity than standard inhibitor ascorbic acid (inhibition:
T271 47673-47681 Sentence denotes 88.20%).
T272 47682-47869 Sentence denotes SAR investigation was concluded as that the presence of benzene on the thiazole ring and phenylthiocarbamoyl moiety along with core pyrazolone group was benefit to the antioxidant effect.
T273 47870-47972 Sentence denotes Additionally, 4-phenyl substituent group on the thiazole ring was better than the methyl substitution.
T274 47973-48140 Sentence denotes Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (MTB) and embodies one of the leading causes of death around the world [107] .
T275 48141-48307 Sentence denotes The dangerous spread of TB is primarily because of its association with HIV infection and to the rapid development of multidrug-resistant (MDR) strains of MTB [108] .
T276 48308-48396 Sentence denotes Pyrazolone as the precursor has been reported to show potential antitubercular activity.
T277 48397-48518 Sentence denotes Sivakumar et al. [109] prepared two series of hybridized pyrazolone analogues and determined their antitubercular effect.
T278 48519-48630 Sentence denotes The most potent compounds 151 and 152 (Fig. 15 ) possessed apparent antitubercular effects (IC 50 < 0.1 mg/mL).
T279 48631-48851 Sentence denotes Furthermore, SAR investigation indicated that the antitubercular activity of the compounds was markedly improved in the absence of double bond in the imine side chain and the benzene ring at the end of pyrazolone moiety.
T280 48852-49046 Sentence denotes Pethaiah et al. [110] synthesized several 2-aryl-5-methyl-2,3dihydro-1H-3-pyrazolone analogues in water through one-pot process and investigated the antitubercular activity against MTB in vitro.
T281 49047-49141 Sentence denotes The MIC value of potential compound 153 (Table 11 ) (Fig. 15 ) was better than clinical drugs.
T282 49142-49247 Sentence denotes SAR showed that the replacement on the N-aryl ring of derivatives contributed antimycobacterial activity.
T283 49248-49471 Sentence denotes Specifically, the analogues containing electron-withdrawing groups with halogens and nitro groups showed stronger activity compare with aryl rings containing electron-donating groups such as methoxide, methyl and isopropyl.
T284 49472-49599 Sentence denotes Daniele et al. [111] prepared various pyrazole analogues and evaluated their antitubercular activities against M. tuberculosis.
T285 49600-49666 Sentence denotes Compound 154 (Fig. 15 ) was the most potent candidate (Table 11 ).
T286 49667-49862 Sentence denotes SAR study demonstrated that the halogens on phenyl ring and the methyl group at third position of pyrazole ring showed higher antitubercular effect than that contained alkyl in the same position.
T1 49863-49962 Sentence denotes Two series of new pyrazolone analogues were prepared and assessed for the anti-MTB activity [112] .
T2 49963-50100 Sentence denotes Two analogues 155 and 156 (Fig. 15 ), containing the p-chlorophenyl ring, were regarded as the most promising MTB inhibitors (Table 11) .
T3 50101-50207 Sentence denotes Meanwhile, the presence of N-methyl-piperazine and morpholine groups remarkedly improved anti-MTB effects.
T4 50208-50295 Sentence denotes Several Mannich bases and Schiff bases of pyrazolone framework were synthesized [113] .
T5 50296-50496 Sentence denotes The results showed that analogue 157 (Fig. 15 ) could be used as a potential antitubercular drug due to its extremely high activity (Table 11 ) over that of the standards ethambutol and ciprofloxacin.
T6 50497-50695 Sentence denotes SAR study revealed that derivatives with acyl substituent had better anti-MTB ability than those comprising EWGs such as nitro, chlorine, and carboxyl and electron donating group including hydroxyl.
T7 50696-51098 Sentence denotes Ahsan and co-workers [114] designed some diversified pyrazolone derivatives aiming at MTB and isoniazid resistant MTB, among which compounds 158 and 159 (Fig. 15 ) exhibited pronounced inhibitory effect (Table 11) , the outstanding inhibitory effect of 159 against isoniazid resistant MTB strain was observed as well and the compound 158 was revealed to show strong antibacterial effect simultaneously.
T8 51099-51341 Sentence denotes SAR study revealed that N-aryl with electronegative substituent group showed strongest antitubercular potency, in which 4-pyridinyl group had maximum inhibition, compared to 2-chlorophenyl, 4-chlorophenyl and 4-aminophenyl group substitution.
T9 51342-51471 Sentence denotes The electron donating group such as 4- methoxyphenyl, 2-methylphenyl, 3-methylphenyl and 4methylphenyl exhibited less inhibition.
T10 51472-51665 Sentence denotes In the follow up research [115] , the potent compound 160 (Fig. 15 ) was selected from the novel synthesized analogues with excellent activity and free from cytotoxicity (>62.5 mg/mL) appeared.
T11 51666-51839 Sentence denotes Better drug-likeness was obtained after adding the imine group between the oxadiazol and the phenyl ring and SAR was summarized as that EWGs produced more inhibitory effect.
T12 51840-51918 Sentence denotes Multiple viruses widely exist in the nature and threaten public health [116] .
T13 51919-52142 Sentence denotes Pyrazolone has been used to generate antiviral agents, involving in anti-orthopoxvirus, anti-protease-resistant prion protein (PrP-res), anti-severe acute respiratory syndrome (SARS) and anti-buffalopox virus (BPXV) agents.
T14 52143-52290 Sentence denotes Fan et al. [117] synthesized a series of pyrimidine-pyrazolone nucleoside chimera analogues and determined the antiorthopoxvirus activity in vitro.
T15 52291-52413 Sentence denotes The consequence proved that compounds 161 and 162 (Fig. 16 ) exerted the most potent antiorthopoxvirus effect (Table 12 ).
T16 52414-52506 Sentence denotes SAR study revealed that the activity was enhanced after matching with the pyrazolone moiety.
T17 52507-52893 Sentence denotes In 2007, Kimata and co-workers [118] reported the synthesis and assessment of multiple PrP-res accumulation inhibitors according to the structure of edaravone, in which the most potent compound 163 (Fig. 16 ) displayed PrP-res inhibitory effect in the ScN2a cells with IC 50 value of 3 nM, which was 130 times more active than quinacrine and more than 300-fold effective than edaravone.
T18 52894-53047 Sentence denotes Furthermore, no significant SOD (superoxide dismutase)-like activity was observed, indicating potential novel mechanism of the PrP-res inhibitory effect.
T19 53048-53332 Sentence denotes SAR study demonstrated that the position and class of substitutions were not directly related to the potency of suppressing the accumulation of PrP-res but substituted the nucleus with 1-cyclohexyl, 3-isopropenyl, 3-(4-nitrophenyl) and 4-benzoyl could enhance the inhibitory activity.
T20 53333-53455 Sentence denotes Srinivasan and teammates [119] synthesized several spiropiperidinyl pyrazolone derivatives inspired from the skeleton of .
T21 53456-53542 Sentence denotes 16) were the most potent analogues with electron donating groups on the aromatic ring.
T22 53543-53900 Sentence denotes Kumar and coworkers [120] synthesized multiple pyrazolone analogues as SARS-coronavirus (CoV) and Middle East Respiratory Syndrome (MERS)-CoV 3C-like protease inhibitors, among which compounds 167 and 168 (Fig. 16 ) exerted the strongest inhibitory effects against SARS and MERS with IC 50 values of 6.4 and 5.8 mM (167), 5.8 and 7.4 mM (168), respectively.
T23 53901-54152 Sentence denotes SAR study revealed that the carboxylate group is a crucial pharmacophore and its presence either at the C-2 position of ring A or moiety B is critical for the activity, meanwhile, the chlorine at C-5 position of ring A slightly decreases the activity.
T24 54153-54348 Sentence denotes It can be seen from the docking studies that pyrazolone group in both compounds 167 and 168 played important roles to form H-bonds with residues Glu 166 and His 41 in SARS 3CL pro , respectively.
T25 54349-54460 Sentence denotes With the change of people's lifestyle and dietary structure, the incidence of fatty liver is increasingly high.
T26 54461-54574 Sentence denotes In particular, nonalcoholic fatty liver disease (NAFLD) has seriously endangered people's life and health [121] .
T27 54575-54667 Sentence denotes However, due to the complex pathogenesis [122] , it is often neglected in clinical practice.
T28 54668-54807 Sentence denotes Pyrazolinone derivatives can reduce cholesterol and lipid accumulation in the body by regulating multiple indicators, such as AMPK and FXR.
T29 54808-54918 Sentence denotes Therefore, it is of importance to improve the lipidlowering activity by modifying the structure of pyrazolone.
T30 54919-55190 Sentence denotes The pyrazolone derivatives are also reported to be the selective antagonists to the nonsteroidal farnesoid X receptor (FXR) [123] , which maintains the bile acid homeostasis and plays crucial roles in the control of cholesterol, lipid, and glucose metabolism [124, 125] .
T31 55191-55281 Sentence denotes Based on the screen of the known FXR modulators, the lead compound 169 (Fig. 17 ) (IC 50 :
T32 55282-55376 Sentence denotes 69.01 mM) was identified with the help of homogeneous time-resolved fluorescence (HTRF) assay.
T33 55377-55447 Sentence denotes On the basis of 169, further modification was carried out accordingly.
T34 55448-55488 Sentence denotes The most promising compound 170 (IC 50 :
T35 55489-55642 Sentence denotes 8.96 mM) displayed antagonistic capability 10-fold and 8-fold higher than that of the control Zguggulsterone and the original analogue 169, respectively.
T36 55643-55803 Sentence denotes Compound 170 was further proved to interact with FXRaLBD with high binding affinity, and potent antagonistic activity against FXR in two cell testing platforms.
T37 55804-55920 Sentence denotes In addition, compound 170 strongly inhibited the regulating activities of chenodeoxycholic acid on FXR target genes.
T38 55921-56100 Sentence denotes Furthermore, compound 170 was proved to play a role in lowering the contents of triglyceride and cholesterol in human hepatoma HepG2 cells and in the cholesterol-fed C57BL/6 mice.
T39 56101-56348 Sentence denotes SAR can be interpreted that changes of substituents on the 1, 3, and 4-positions of pyrazolone group had crucial influence on antagonistic effect, and appropriate structural optimizations on the above regions can substantially strengthen activity.
T40 56349-56410 Sentence denotes NAFLD is a clinical syndrome identified by hepatic steatosis.
T41 56411-56480 Sentence denotes It is closely linked to obesity, insulin resistance and dyslipidemia.
T42 56481-56617 Sentence denotes AMPactivated protein kinase (AMPK) functions as an energy sensor and plays an important role in regulating lipid metabolism [126, 127] .
T43 56618-56832 Sentence denotes According to the structure of lead compound 171 (Fig. 17) , Zhang et al. [128] synthesized multiple pyrazolone derivatives as AMPK activators to suppress lipid synthesis and reduce lipid accumulation in ob/ob mice.
T44 56833-57106 Sentence denotes The most potent compound 172 directly activated the kinase domain of AMPK with an EC 50 value of 2.1e0.2 mmol/L and acted as a non-selective activator of AMPK complexes, additionally, compound 172 suppressed the accumulation of triglyceride in HepG2 cells dose-dependently.
T45 57107-57234 Sentence denotes The outcome demonstrated that the AMPK activators could be part of a treating method for NAFLD and related metabolic disorders.
T46 57235-57380 Sentence denotes Diabetes is considered to be relative to overindulgent life-style and thus is thought as major health concern in industrialized countries [129] .
T47 57381-57523 Sentence denotes Pyrazolones have been disclosed to be antihyperglycemic through multiple targets including aldose reductase (AR), a-glucosidase and a-amylase.
T48 57524-57864 Sentence denotes The antihyperglycemic activity of pyrazolone derivatives was explored by Kees et al. [130] The potent compound 173 (100 mg/kg) (Fig. 18 ) caused a 68% decrease in plasma glucose in db/db mice, moreover, it essentially normalized the level of glucose at 20 mg/kg (57% reduction) and maintained remarkable reduction at 2 mg/kg (30% decrease).
T49 57865-58110 Sentence denotes SAR could be concluded that the substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C-4, in combination with trifluoromethyl at C-4 position of pyrazolone (hydroxy tautomer) formed potent antihyperglycemic agents in mice.
T50 58111-58304 Sentence denotes In addition, the chemical "trapping" of four of the seven possible tautomeric forms of the heterocycle by mono-and dialkylation at the acidic hydrogens gave several additional potent analogues.
T51 58305-58496 Sentence denotes Kadam and co-workers [129] synthesized several pyrazolone derivatives as inhibitors of AR, in which compound 174 (Fig. 18) displayed the most promising inhibitory with IC 50 value of 6.30 mM.
T52 58497-58712 Sentence denotes In regard to SAR, it was possible to note that the hydrophobic groups like benzene ring with pyrazolone adversely influenced AR inhibition, while the introduction of carbothioamide group increased inhibitory effect.
T53 58713-58954 Sentence denotes Because of the simultaneous existing of arbothioamide moiety and 3-(4I-methoxyphenyl)-1-phenyl-1Hpyrazole and 3-(4I-chlorophenyl)-1-phenyl-1H-pyrazole substituent group at first position of pyrazolone, compound 174 exerted the best activity.
T54 58955-59319 Sentence denotes Docking analysis suggested that substituted groups of 174 gave the proper placement of hydrophobic groups in respective binding pockets of AR, avoiding the poor interactions because the size of substitutions was too small to occupy the binding pocket, and the pyrazolone moiety in compound 174 was considered to play a role in form H-bond with the residue Cys 298.
T55 59320-59557 Sentence denotes Eldebss and colleagues [131] prepared a series of pyrazolones acting as a-glucosidase and a-amylase inhibitors, among which compound 175 (Fig. 18) compound 176 (Fig. 18 ) displayed the strongest inhibitory effect with the ratio of 61.6%.
T56 59558-59794 Sentence denotes The primary SAR can be suspected as that introduction of disubstituted halogen analogues promoted the inhibitory effect due to its high electronegativity, moreover, multifluoro substitution on A ring could be the potential active group.
T57 59795-60178 Sentence denotes In addition to the activities mentioned above, pyrazolones have been shown to inhibit the proteins including K ATP channel protein, phosphodiesterase (PDE), aromatase, divalent metal transporter 1 (DMT1), human carboxylesterase1 (hCE1) and transforming growth factor (TGF) bR1, indicating the multiple targets therapeutic action and favorable drug-likeness of pyrazolone derivatives.
T58 60179-60407 Sentence denotes Drizin and co-workers [133] designed and synthesized a cluster of pyrazolone derivatives as K ATP channel openers inspired from disclosed compounds (the skeleton of 177 and 178, Fig. 19 ), together with the investigation of SAR.
T59 60408-60541 Sentence denotes It can be concluded that cyclopentanone in the left hand portion (A area) of the derivative was 4fold more potent than cyclohexanone.
T60 60542-60712 Sentence denotes The introduction of gemdimethyl groups as well as incorporation of oxygen in the cyclohexanone ring in the left hand portion of the molecule elevated the potency 10-fold.
T61 60713-60853 Sentence denotes In the right hand portion of the molecule, the activity was promoted 5-fold when the NH-group on the pyrazolone was replaced by oxygen atom.
T62 60854-61142 Sentence denotes Ochiai et al. [87] synthesized several 4,4-dimethylpyrazolone analogues as cyclic 30,50-nucleotide PDE 3/4-inhibitor, in which the compound 179 (Fig. 19 ) was demonstrated to be the most potent compound inhibiting PDE 3A and PDE 4B with the IC 50 values of 0.14 and 0.15 mM, respectively.
T63 61143-61206 Sentence denotes In addition, significant bronchodilatory activity was observed.
T64 61207-61469 Sentence denotes SAR study demonstrated that the presence of pyrazolopyridine 7-substituent can engender potency for the inhibition of PDE 4, and the isosteric imidazopyridine substitution made for the pyrazolopyridine subunit increases the well-balanced dual of PDE 3 and PDE 4.
T65 61470-61695 Sentence denotes As a member of PDEs, Trypanosoma brucei PDB1 (TbrPDEB1) was described as a crucial target for the therapy of Human African trypanosomiasis [134, 135] , which was a parasitic disease caused by the protozoan pathogen T. brucei.
T66 61696-61818 Sentence denotes Orrling and colleagues [136] explored catechol pyrazolinones as trypanocidals inspired from the structural motif rolipram.
T67 61819-61941 Sentence denotes After the scaffold merging, the premier potent compound 180 (Fig. 19) was selected with the TbrPDEB1 IC 50 value of 12 mM.
T68 61942-62408 Sentence denotes Furthermore, with the help of homology modeling and docking studies to guide fragment growing into the parasite-specific Ppocket, which was a unique sub-pocket that extended from the invariant glutamine (Gln 874) through the protein to the solvent in the enzyme binding site, the fragment growing compound 181 (Fig. 19) was emerged with the outstanding activities for inhibiting T. brucei rhodesiense with IC 50 value of 60 nM and TbrPDEB1 with IC 50 value of 49 nM.
T69 62409-62577 Sentence denotes SAR investigation elucidated that pyrazolone held a conjugated p-system and additional possibility to interact with aromatic residues in the binding pocket of TbrPDEB1.
T70 62578-62796 Sentence denotes Moreover, the extended alkyl chain in the analogues of 181 enabled to reach and enter the P-pocket, which displaced water from the length of the P-pocket and placed the tetrazole at the solventexposed exit of the pore.
T71 62797-62894 Sentence denotes The tetrazole in compound 181 formed a H-bond with Tyr 845, further stabilizing the conformation.
T72 62895-63292 Sentence denotes Afterwards, according to the structure of 180 and 181, Amata and coworkers [137] designed and synthesized a cluster of derivatives, while poor inhibitory effect was detected, the most promising pyrazolone compound 182 (Fig. 19 ) only showed inhibition for 18% at the dose of 10 mM, indicating a better understanding of the subtle structural features was necessary for an optimal enzyme inhibition.
T73 63293-63413 Sentence denotes Yi and co-workers [138] synthesized the diversified pyrazolone derivatives and screened the aromatase inhibition effect.
T74 63414-63525 Sentence denotes The most active compounds were 183 and 184 (Fig. 19) , showing IC 50 values of 2.3 nM and 3.3 nM, respectively.
T75 63526-63612 Sentence denotes The inhibition of compound 183 was even stronger than the reference letrozole (IC 50 :
T76 63613-63621 Sentence denotes 2.8 nM).
T77 63622-63726 Sentence denotes SAR analysis indicated that the pyrazolone moiety could inhibit aromatase by binding to its active site.
T78 63727-63993 Sentence denotes The bioactivity result proved that the presence of substitutions in compounds 183 and 184 were good for the inhibition, as for the most promising compound 183, the cyano group was revealed to interact with the important residues Arg 115 and Met 374 of the aromatase.
T79 63994-64072 Sentence denotes From the high-throughput screening of DMT1 [139] , pyrazolone hit 185 (IC 50 :
T80 64073-64131 Sentence denotes 2.57 mM, Fig. 19 ) was elaborated as the structural motif.
T81 64132-64202 Sentence denotes Preliminary hit-to-lead efforts gave the pyridyl analogue 186 (IC 50 :
T82 64203-64409 Sentence denotes 1.53 mM), which imparted several undesirable features including most notably an extended conjugation motif affording an intense orange color as well as Michael acceptor features at the benzylidene a-carbon.
T83 64410-64533 Sentence denotes Further investigation introduced more substitutions to modify these skeletons, and the most promising compound 187 (IC 50 :
T84 64534-64798 Sentence denotes 0.64 mM) was distinguished because of its eminent absorption, distribution, metabolism and excretion (ADME) properties, the inhibition of CYP3A4 was significantly reduced and the rat microsome metabolic stability was markedly hoisted compared to the precursor 186.
T85 64799-64917 Sentence denotes SAR of the analogues of 187 implied that EWGs on the benzene ring were slightly preferred over electron-donating ones.
T86 64918-65213 Sentence denotes Based on the existing TGFbR1 inhibitors, Guckian and colleagues [140] described a series of TGFbR1 kinase inhibitors including a pyrazolone group which allowed replacement of the ubiquitous nitrogen H-bond acceptor within the core with a carbonyl without remarkable loss in biochemical activity.
T87 65214-65371 Sentence denotes The most active compound 188 (Fig. 19 ) inhibited the TGFbR1 kinase with the Ki value of 0.012 mM and suppressed the PAI-Luc with the IC 50 value of 0.22 mM.
T88 65372-65523 Sentence denotes SAR can be recapitulated that the carbonyl moiety of pyrazolone was potent to capture the H-bonding interaction with the key residue Lys 232 of TGFbR1.
T89 65524-65767 Sentence denotes The A ring was the area the authors paid attention to modify, and they found that when A ring was substituted as pyridine ring could elevate the activity because it contained a basic nitrogen in the 2-position to occupy the hydrophobic pocket.
T90 65768-66208 Sentence denotes As for the aromatics on A ring, substitutions on meta position was proved to be superior to ortho or para position, and this position was very sensitive to the nature of substitution with preference for small hydrophobic substituent groups without branching on the a-carbon, considering to influence of the size of substituted atom on the hydrophobic pocket, bromo group was selected for the suitable substitution for further investigation.
T91 66209-66452 Sentence denotes Asymmetric synthesis asymmetric spiro-pyrazolone derivatives have been a hotspot in recent years, while the investigations of bioactivity about these productions and the relationships between their enantioisomerism and activity are still rare.
T92 66453-66587 Sentence denotes Bao et al. [141] synthesized a series of dispirotriheterocyclic scaffold derivatives and screened the inhibitory effects against hCE1.
T93 66588-66909 Sentence denotes It is worth noting that the most potent compound 189 (Fig. 19) , in which there were two chiral centers important for inhibitory potency, exerted the strong inhibition with IC 50 value of 0.39 mM, whose activity was 20fold stronger than its enantiomer, indicating the importance of asymmetric [3 þ 2] cyclization process.
T94 66910-67068 Sentence denotes Pyrazolone core is one of the most explored precursors among diverse fused heterocycles, capable of multiple roles in different pathophysiological conditions.
T95 67069-67444 Sentence denotes According to the concept of generalized bioisosteres [142, 143] , as a typical synthetic rather than natural motif in medicinal chemistry, pyrazolone is potential to replace multiple moieties with similar chemical structure and bioactivities including parazole, imidazolin-5-one and 2,4-dihydro-1,2,4-triazol-3-one, etc., providing an important scaffold for drug development.
T96 67445-67739 Sentence denotes Being a versatile molecule with immense biological significance, pyrazolone derivatives are being developed for several pathological screening including antimicrobial, antitumor, CNS effect, anti-inflammatory, antioxidant, antitubercular, antiviral and protein inhibitors activities since long.
T97 67740-68053 Sentence denotes The development of pyrazolone derivatives can be regarded as the epitome of medicinal chemistry, starting from antipyrine, several analogues have been explored and the precursor designing methods have evolved from structural modification to Fragment Based Drug Design and high-throughput screening simultaneously.
T98 68054-68303 Sentence denotes With the development of science, machine learning, virtual screening and combinatorial chemistry technologies shorten the time of filtrating the leading compounds and will play a more and more important role in drug design in the future [144, 145] .
T99 68304-68413 Sentence denotes Investigations for privileged scaffold from the perspective of SAR have been lasting several years [146e151].
T100 68414-68573 Sentence denotes It is probable that pyrazolone scaffold has its position in the establishment of compound library due to its good drug-likeness and broad bioactive properties.
T101 68574-68964 Sentence denotes Moreover, as we mentioned in this article, the pyrazolone group maintains properties like aromatic and it is feasible to form pi-alkyl effect with residues in the potential target, and the carbonyl group in pyrrazole is a favorable hydrogen acceptor which is feasible to form potential H-bond, which provide evidence for the importance of pyrazolone structural motif in medicinal chemistry.
T102 68965-69130 Sentence denotes Pan Assay Interference Compounds studies consider that some poor drug-likeness compounds bring false positive results [152, 153] , but pyrazolone is not on the list.
T103 69131-69345 Sentence denotes Besides, the toxicity of pyrazolone derivatives is still alarming [154] , because the loss and harm caused by the side effects of antipyrine and aminopyrine including leukopenia and agranulocytosis are still vivid.
T104 69346-69564 Sentence denotes In this review, we have disclosed recent role of pyrazolones in the field of medicinal chemistry by discussing insights of SAR studies and binding conformations of these heterocycle compounds with a variety of targets.
T105 69565-69694 Sentence denotes These intelligences are helpful to explore novel pyrazolone analogues for the challenging pathophysiological conditions nowadays.
T106 69695-69757 Sentence denotes None of the authors have any conflict of interest to disclose.
T107 69759-69806 Sentence denotes lung cancer cell lines ABTS 2,2 0 -azinobis (3-