LitCovid-sentences  

PMC:7461420 / 63068-75887 JSONTXT 8 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T547 0-40 Sentence denotes 3.1.7 Small molecule inhibitors of Mpro
T548 41-161 Sentence denotes Benzotriazole esters (88–91; Figure 26) were discovered as novel nonpeptidic irreversible inhibitors of SARS‐CoV‐1 Mpro.
T549 162-279 Sentence denotes 168 Among them, 91 exhibited the best enzymatic inhibitory activity, but no antiviral activity in cell‐based assays.
T550 280-389 Sentence denotes The covalent binding mode of 91 was confirmed by electrospray ionization mass spectrometry (ESI‐MS) analyses.
T551 390-445 Sentence denotes Figure 26 Active esters as SARS‐CoV‐1 Mpro inhibitors.
T552 446-715 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus With a slight structural modification from benzotriazole ester, Zhang et al. reported a series of active halopyridyl esters containing thiophene, furan, and indole moieties (92–95; Figure 26).
T553 716-802 Sentence denotes Among them, 93 displayed the highest enzymatic inhibitory activity at SARS‐CoV‐1 Mpro.
T554 803-874 Sentence denotes 169 However, no antiviral activity for this compound was communicated.
T555 875-944 Sentence denotes The irreversible binding mode of 93 was confirmed by ESI‐MS analysis.
T556 945-955 Sentence denotes 170 , 171
T557 956-968 Sentence denotes Ghosh et al.
T558 969-1144 Sentence denotes 172 studied the SARs of halopyridinyl indole carboxylates and identified a series of analogs (96–101; Figure 27) as SARS‐CoV‐1 Mpro inhibitors in the nanomolar potency range.
T559 1145-1264 Sentence denotes The best derivative (100) had high enzymatic inhibitory potency (IC50, 0.030 µM) and antiviral activity (EC50, 6.9 µM).
T560 1265-1383 Sentence denotes Compound 97 was also observed to inhibit the MERS‐CoV Mpro both in enzymatic and cell‐based (EC50, 12.5 µM) bioassays.
T561 1384-1470 Sentence denotes 173 This molecule covalently modified Mpro, which was confirmed by MALDI‐TOF studies.
T562 1471-1553 Sentence denotes Figure 27 SAR of halopyridinyl indole carboxylates as SARS‐CoV‐1 Mpro inhibitors.
T563 1554-1792 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus 5‐Halopyridinyl esters are troublesome drug candidates because of their potential for rapid hydrolysis by various esterases and other enzymes in mammalian cells.
T564 1793-1903 Sentence denotes They can potentially also react nonspecifically with other thiols and nucleophiles, a recipe for cytotoxicity.
T565 1904-1984 Sentence denotes To bypass this problem by developing stable noncovalent inhibitors, Zhang et al.
T566 1985-2166 Sentence denotes 174 reported a group of methylene ketones and analogous mono‐ and di‐fluorinated methylene ketones based on pyridinyl esters (102 and 103; Figure 28) as SARS‐CoV‐1 Mpro inhibitors.
T567 2167-2305 Sentence denotes Enzymatic investigations and ESI‐MS experiments illustrate that those inhibitors bind to their target in a noncovalent, reversible manner.
T568 2306-2385 Sentence denotes Figure 28 Etacrynic acid and isatin derivatives as SARS‐CoV‐1 Mpro inhibitors.
T569 2386-2628 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus An HPLC‐based screening of electrophilic compounds identified the etacrynic acid‐derived amide 106 and ester 107 as SARS‐CoV‐1 Mpro inhibitors with moderate potency.
T570 2629-2870 Sentence denotes 175 Etacrynic carboxamide (105; K i, 35.3 µM) bound more strongly to SARS‐CoV‐1 Mpro than to papain protease, while etacrynic acid ester 104 was more active at papain protease (K i, 3.2 µM) than at SARS‐CoV‐1 Mpro (K i, 45.8 µM; Figure 28).
T571 2871-2957 Sentence denotes SAR studies suggested that chloro substituents were necessary for protease inhibition.
T572 2958-3097 Sentence denotes Docking studies of 105 to Mpro revealed that it forms hydrogen bonds with Gln189, Glu166, Thr190, and Gln192 with its terminal amino group.
T573 3098-3219 Sentence denotes The Michael system carbonyl group interacts with Gly143, and the reactive double bond remained next to the Cys145 sulfur.
T574 3220-3317 Sentence denotes Previously, isatin (2,3‐dioxoindole) derivatives were observed to inhibit rhinovirus 3C protease.
T575 3318-3466 Sentence denotes 176 Due to the structural similarity between the rhinovirus 3C protease and SARS‐CoV‐1 Mpro, these derivatives were tested against SARS‐CoV‐1 Mpro.
T576 3467-3606 Sentence denotes Among them, 106 (IC50, 0.95 µM) and 107 (IC50, 0.98 µM) exhibited the best SARS‐CoV‐1 Mpro inhibitory activity in the low micromolar range.
T577 3607-3765 Sentence denotes 176 SAR studies suggested that the inhibition efficiency was mainly reliant on hydrophobic and electronic properties of the isatin core substitution pattern.
T578 3766-3854 Sentence denotes Docking studies revealed that the molecules fit well in the active site of the protease.
T579 3855-3959 Sentence denotes Both carbonyl groups of the isatin core engaged in H‐bonds with NH of Gly143, Ser144, Cys145, and His41.
T580 3960-4182 Sentence denotes Compounds 106 and 107 176 were more selective for SARS‐CoV‐1 Mpro than other proteases like papain (106, 103 µM; 107, 87.24 µM), chymotrypsin (106, ~1 mM; 107, 10.4 µM), and trypsin (106, 362 µM; 107, 243 µM; Figure 28).
T581 4183-4253 Sentence denotes Zhou et al. extended the SAR studies for further activity improvement.
T582 4254-4339 Sentence denotes Compound 108 bearing carboxamide showed the best SARS‐CoV‐1 Mpro inhibitory activity.
T583 4340-4430 Sentence denotes However, this derivative did not bind covalently to the Cys145 residue of the active site.
T584 4431-4568 Sentence denotes 177 Further structural investigations at the carboxamide of 108 with a variety of substituted sulfonamides did not improve the activity.
T585 4569-4626 Sentence denotes Compound 109 was the best one of that series (Figure 28).
T586 4627-4630 Sentence denotes 178
T587 4631-4799 Sentence denotes The modification of 110, identified by high‐throughput screening (HTS; Figure 29), led to pyrazolone and pyrazole derivatives 111 and 112 as SARS‐CoV‐1 Mpro inhibitors.
T588 4800-4851 Sentence denotes 179 , 180 Taking these as leads, Ramajeyam et al.
T589 4852-4972 Sentence denotes 181 reported compounds 112–114 to be the best‐performing inhibitors of the series(IC50 5.5, 6.8, 8.4 µM, respectively).
T590 4973-5040 Sentence denotes They also observed moderate inhibitory activity against CVB3 3Cpro.
T591 5041-5205 Sentence denotes Structure‐functionality analyses illustrated that the benzylidene ring next to pyrazolone C4 in addition to electron‐withdrawing groups, favors inhibitory activity.
T592 5206-5400 Sentence denotes Molecular modeling studies of 112 predicted that for its inhibitory function, the N1‐phenyl residue in the Mpro S1 site as well as the carboxyl benzylidene moiety in the S3 pocket are important.
T593 5401-5468 Sentence denotes Figure 29 Pyrazoles and pyrimidines as SARS‐CoV‐1 Mpro inhibitors.
T594 5469-5681 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Kumar et al. described furan‐inserted pyrazolone derivatives as dual SARS‐CoV‐1 Mpro and MERS‐CoV Mpro inhibitors (115–118; Figure 29).
T595 5682-5761 Sentence denotes 182 Compounds 115, 117, and 118 exhibited the best dual inhibitory activities.
T596 5762-5879 Sentence denotes Compounds 115 and 116 also displayed inhibitory activity against H5N1 neuraminidase (IC50 2.8, 2.9 µM, respectively).
T597 5880-5991 Sentence denotes 183 Ramajeyam et al. also disclosed a range of pyrimidine derivatives as SARS‐CoV‐1 Mpro inhibitors (119–121).
T598 5992-6062 Sentence denotes Compound 121 showed high inhibitory potency with an IC50 value 6.1 µM.
T599 6063-6066 Sentence denotes 181
T600 6067-6248 Sentence denotes HTS of NIH molecular libraries (~293 000 substances) yielded the dipeptide 122 containing 3‐pyridyl as hit compound against SARS‐CoV‐1 Mpro with an IC50 value of 2.2 µM (Figure 30).
T601 6249-6343 Sentence denotes Preliminary SAR studies identified 123 and 124 as the most promising inhibitors of the series.
T602 6344-6354 Sentence denotes 184 , 185
T603 6355-6425 Sentence denotes Figure 30 Simple dipeptide derivatives as SARS‐CoV‐1 Mpro inhibitors.
T604 6426-6699 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus The X‐ray crystal structure of 123 attached to SARS‐CoV‐1 Mpro highlighted the compound's identical orientation in the pocket to that of established covalent peptidomimetic inhibitors (Figure 31).
T605 6700-6785 Sentence denotes The compound with an R‐configuration occupied the S3‐S1' subsites of SARS‐CoV‐1 Mpro.
T606 6786-7127 Sentence denotes Indeed, only (R)‐123 was able to inhibit the Mpro enzyme with an IC50 value of 1.5 µM, while the (S)‐enantiomer was inactive. (R)‐123 inhibited SARS‐CoV‐1 Mpro in a competitive manner (K i, 1.6 µM) with a noncovalent mode of inhibition. (R)‐123 also showed antiviral activity (12.9 µM) in mock infected and SARS‐CoV‐1 infected Vero E6 cells.
T607 7128-7229 Sentence denotes Figure 31 The X‐ray crystal structure of 123 bound to the binding pocket of SARS‐CoV‐1 Mpro (PDB ID:
T608 7230-7236 Sentence denotes 3V3M).
T609 7237-7268 Sentence denotes Pockets S1'–S3 are highlighted.
T610 7269-7592 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com] To enhance the inhibitory activity, SAR study efforts around P1' of 123 provided compounds containing imidazole (125) and 5‐chlorofuran (126) with equipotent activity to lead 123 (Figure 30).
T611 7593-7746 Sentence denotes Next, the exploration of P1 3‐pyridyl unit of 123 revealed pyridazine (127) and pyrazine (128) which were only tolerated, albeit without any improvement.
T612 7747-7981 Sentence denotes The same group of researchers discovered potent, noncovalent SARS‐CoV‐1 Mpro blockers based on a benzotriazole scaffold in an MLPCN screening, 186 resulting in hit compound 129 (Figure 32) with a SARS‐CoV‐1 Mpro IC50 value of 6.2 µM.
T613 7982-8058 Sentence denotes Figure 32 SARS‐CoV‐1 Mpro inhibitors containing the benzotriazole scaffold.
T614 8059-8227 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus SAR studies focusing on the benzotriazole moiety of 129 were performed to improve activity.
T615 8228-8349 Sentence denotes The replacement of this group with 4‐phenyl‐1,2,3‐triazole (as in 130) was somewhat tolerated (IC50 of 11 µM; Figure 32).
T616 8350-8570 Sentence denotes Further modifications to the acetamide (P2‐P1' region) resulted in molecules bearing a thiophene ring on one side and a branched i‐propyl amide (131) or cyclobutylamide (132) on the other—reaching IC50 values below 5 µM.
T617 8571-8704 Sentence denotes To cut overall molecular weight of the inhibitors, P3‐truncation was performed, which led to potent derivatives (133–137; Figure 32).
T618 8705-8768 Sentence denotes Compound 137 displayed extremely high inhibition (IC50, 51 nM).
T619 8769-8839 Sentence denotes SARS‐CoV‐1 Mpro inhibitors were also discovered from medicinal plants.
T620 8840-8859 Sentence denotes In 2011, Ryu et al.
T621 8860-8935 Sentence denotes 187 disclosed a range of inhibitors obtained from Torreya nucifera leaves.
T622 8936-9089 Sentence denotes Of all the isolated chemicals, the biflavone, amentoflavone (138; Figure 33), was identified as a potent noncompetitive inhibitor with an IC50 of 8.3 µM.
T623 9090-9191 Sentence denotes Docking studies of 138 identified the interactions of Val186 and Gln192 as major sites at the target.
T624 9192-9288 Sentence denotes Figure 33 Flavone and terpenoid derivatives with inhibitory activity against SARS‐CoV‐1 3CLpro.
T625 9289-9471 Sentence denotes 3CLpro, 3C‐like protease; SARS‐CoV, severe acute respiratory syndrome coronavirus They also isolated a series of terpenoids from T. nucifera as anti‐SARS‐CoV Mpro agents (Figure 33).
T626 9472-9549 Sentence denotes 187 Among them, ferruginol (139; IC50 49.6 µM) was the most active compound.
T627 9550-9791 Sentence denotes Additionally, they isolated quinone‐methide triterpenoids celastrol (140), pritimererin (141), and tingenone (142) from methanol extracts of Tripterygium regelii which exhibited fair inhibition activity (IC50 2.6, 9.9, 5.5 µM, respectively).
T628 9792-9926 Sentence denotes SAR studies indicated that for effective inhibition, the quinone‐methide group in ring A and the more lipophilic ring E were critical.
T629 9927-10009 Sentence denotes All compounds were characterized as competitive inhibitors using kinetic analyses.
T630 10010-10020 Sentence denotes Wen et al.
T631 10021-10119 Sentence denotes 188 reported abietane‐type diterpenoids and lignoids with a powerful anti‐SARS‐CoV‐1 Mpro effect.
T632 10120-10255 Sentence denotes Especially betulinic acid (143) and savinin (144) effectively inhibited SARS‐CoV‐1 Mpro (K i 8.2 µM, 9.1 µM, respectively) (Figure 33).
T633 10256-10303 Sentence denotes These inhibitors acted in a competitive manner.
T634 10304-10492 Sentence denotes Lu et al. discovered two hit SARS‐CoV‐1 3CLpro inhibitors, sulfone 145 and dihydroimidazole 146, by structure‐based virtual screening of a compound library of 58 855 chemicals (Figure 34).
T635 10493-10624 Sentence denotes 189 The central structural elements of the hits, determined in docking experiments, were then used for additional analog searches.
T636 10625-10684 Sentence denotes Figure 34 Structure of SARS‐CoV‐1 Mpro inhibitors 145–149.
T637 10685-10835 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Computational similarity screening discovered 21 analogs from these hits.
T638 10836-10933 Sentence denotes Among them, the two best compounds 147 and 148 display IC50 values of 0.3 and 3 µM, respectively.
T639 10934-11051 Sentence denotes A variety of SARS‐CoV‐1 Mpro inhibitors have been identified through virtual screening (VS) as an alternative to HTS.
T640 11052-11166 Sentence denotes VS of 50 240 structurally diverse small molecules allowed to identify 104 molecules with anti‐SARS‐CoV‐1 activity.
T641 11167-11318 Sentence denotes Compound 149 (Figure 34) demonstrated potent enzyme inhibition (IC50, 2.5 μM) and an EC50 of 7 μM in Vero cell‐based SARS‐CoV‐1 plaque reduction assays
T642 11319-11434 Sentence denotes Virtual screening identified the serotonin antagonist cinanserin (150, Figure 35) as a potential inhibitor of Mpro.
T643 11435-11519 Sentence denotes It had previously shown activity against SARS‐CoV‐1 Mpro with an IC50 value of 5 µM.
T644 11520-11642 Sentence denotes 190 Subsequent tests revealed its anti‐SARS‐CoV‐2 activity (EC50, 20.6 µM) and an IC50 value of 125 µM (SARS‐CoV‐2 Mpro).
T645 11643-11687 Sentence denotes Figure 35 Covalent bond inhibitors of Mpro.
T646 11688-11899 Sentence denotes Mpro, main protease Their HTS yielded seven primary hits including the approved drugs disulfiram (151) and carmofur (152), as well as ebselen (153), shikonin (154), tideglusib (155), and PX‐12 (156) (Figure 35).
T647 11900-12054 Sentence denotes Using MS/MS analysis, they deduced that ebselen (153) and 156 are irreversible inhibitors of Mpro by covalently attaching to Cys145 of the catalytic dyad.
T648 12055-12131 Sentence denotes Molecular docking was used to illustrate how 151, 154, and 155 bind to Mpro.
T649 12132-12296 Sentence denotes Antiviral activity assays, using real‐time reverse transcription‐PCR, indicated that ebselen and inhibitor “N3” (40; Figure 12) had the strongest antiviral effects.
T650 12297-12411 Sentence denotes Ebselen displayed an EC50 value of 4.67 µM, and “N3” showed an EC50 value of 16.77 µM in a plaque‐reduction assay.
T651 12412-12477 Sentence denotes Ebselen's IC50 value for SARS‐CoV‐2 Mpro was reported at 0.67 µM.
T652 12478-12546 Sentence denotes The activity data of remaining compounds is summarized in Figure 35.
T653 12547-12625 Sentence denotes Ebselen has been studied for an array of diseases and has a very low toxicity.
T654 12626-12697 Sentence denotes 191 , 192 , 193 Its safety has been demonstrated in clinical trials.
T655 12698-12819 Sentence denotes 191 , 192 , 194 It can therefore be considered a promising molecule for the treatment or prevention of CoV infections.