Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems ( las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of 2 drugs, idelalisib in 2014 and copanlisib in 2017. This perspective will discuss medicinal chemistry design approaches to novel isoformselective inhibitors through considering brief case histories of compounds that have progressed 2 either into clinical development or that have revealed new structural motifs in this highly competitive area of research.
P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions including platelet aggregation, smooth muscle cell proliferation and immune regulation. The P2Y receptors belong to the GPCR superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date there have only been a limited number of small molecule P2Y receptor antagonists that have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.