Developing our knowledge of the quinolone scaffold and its value to anticancer drug design

ABSTRACTIntroduction The quinolone scaffold is a bicyclic benzene-pyridinic ring scaffold with nitrogen at the first position and a carbonyl group at the second or fourth position. It is endowed with a diverse spectrum of pharmacological activities, including antitumor activity, and has progressed into various development phases of clinical trials for their target-specific anticancer activity.Areas covered The present review covers both classes of quinolones, i.e. quinolin-2(H)-one and quinolin-4(H)-one as anticancer agents, along with their possible mode of binding. Furthermore, their structure-activity relationships, molecular mechanisms, and pharmacokinetic properties are also covered to provide insight into their structural requirements for their rational design as anticancer agents.Expert opinion Synthetic feasibility and ease of derivatization at multiple positions, has allowed medicinal chemists to explore quinolones and their chemical diversity to discover newer anticancer agents. The presence of both hydrogen bond donor (−NH) and acceptor (-C=O) functionality in the basic scaffold at two different positions, has broadened the research scope. In particular, substitution at the -NH functionality of the quinolone motif has provided ample space for suitable functionalization and appropriate substitution at the quinolone's third, sixth, and seventh carbons, resulting in selective anticancer agents binding specifically with various drug targets.KEYWORDS: Anticancerquinolonequinolin-2(H)-onequinolin-4(H)-onestructure-activity relationship Article highlights The quinolone scaffold is of wide interest in medicinal chemistry, with various quinolone-based antibacterial drugs approved by FDA.Quinolones have apparently exhibited excellent potency against various cancer cell lines.Recently, several quinolone-based compounds have been patented, while four are under clinical development as anticancer agents.Recent advances in the medicinal chemistry of quinolones based anticancer agents along with their SAR and biological studies have been compiled.The SAR analysis have revealed the scope for optimization of the anticancer effect obtain efficient quinolone based anticancer agents in near future.Abbreviations DNA=Deoxyribonucleic acidEDG=Electron Donating GroupEGFR=Epidermal growth factor receptorEWG=Electron Withdrawing GroupGI50=Growth inhibitory power of a drug to inhibit 50% cell growthHDAC=Histone deacetylaseIC50=Concentration of drug at which 50% cell growth is inhibitedLD50=Concentration of drug at which 50% cells dieMTT=(3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)NSCLC=Non small cell lung cancerPBP=Penicillin Binding ProteinPD=PharmacodynamicsPK=PharmacokineticsSAR=Structure activity relationshipTopo=TopoisomeraseTopo2β=Topoisomerase 2 betaWHO=World Health OrganizationFDA=Food & Drug AdministrationPI3K=phosphoinositide-3-kinase–protein kinaseNSCLC=Non-Small Cell Lung CancerDPPH=2,2-diphenyl-1-picrylhydrazylATP=Adenosine triphosphateROS=Reactive oxygen speciesDeclaration of interestThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer DisclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingAuthors express their sincere thanks to Prof. R. P. Tiwari, Vice-Chancellor, Central University of Punjab, Bathinda, for his continous support and providing the state of art facilities. Y Singh and S Thareja are grateful to the Department of Science and Technology of the Government of India for funding the DST-SERB (SRG) project (File No. SRG/2022/000006). V Monga also acknowledge RSM grant (Ref. No: CUPB/Acad./2022/1194) provided by CUPB. The authors also acknowledge the Department of Science and Technology of the Government of India for providing a departmental DST-FIST grant (SR/FST/LSI-656/2016) to the Department of Pharmaceutical Sciences and Natural Products of the Central University of Punjab, India.