ABSTRACT
The evolution of drug-resistant bacteria poses a serious threat to public health; hence, it is imperative to develop new and efficient antibiotics. Irresistin-16 (IRS-16) is a dual-target antibacterial candidate that affects folate biosynthesis and membrane integrity and exhibits potent lethality against various bacteria. In this study, a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (DAPQ) derivatives based on IRS-16 was designed and synthesized to identify outstanding antibacterial candidates. The most promising compound, 7-(4-(4-methylpiperazin-1-yl) benzyl)-7H-pyrrol[3,2-f] quinazoline-1,3-diamine (18 e), displayed excellent antibacterial activity against both gram-positive and gram-negative bacteria (minimum inhibitory concentrations=1-4â µg/mL), improved water solubility, poor hemolytic activity and low cytotoxicity. Compound 18 e exhibited rapid bactericidal properties and prevented bacterial resistance in laboratory simulations. These results provide a basis for the development of new DAPQ-based compounds to combat emerging bacterial resistance.
Subject(s)
Anti-Bacterial Agents , Quinazolines , Anti-Bacterial Agents/pharmacology , Quinazolines/pharmacology , Gram-Positive Bacteria , Gram-Negative Bacteria , Bacteria , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 µM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
Subject(s)
Platelet Aggregation Inhibitors/pharmacology , Quinazolinones/pharmacology , Receptors, Thrombin/antagonists & inhibitors , Cell Survival/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Receptors, Thrombin/metabolism , Structure-Activity RelationshipABSTRACT
Protease activated receptor 4 (PAR4) is a key target in antiplatelet medication to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth while retaining initial thrombus formation by acting on the late diffusion stage of platelet activation, which may provide a safer alternative than other antiplatelet agents. Currently, research on PAR4 antagonists is of increasing interest in the field of antiplatelet agents. This article provides an overview of the discovery and development of small-molecule antagonists of PAR4 as novel antiplatelet agents, including structure-activity relationship (SAR) analysis, progress of structure and bioassay optimization, and the latest structural and/or clinical information of representative small-molecule antagonists of PAR4.
