Quinoline heterocyclic containing plant and marine candidates against drug-resistant Mycobacterium tuberculosis: A systematic drug-ability investigation

Today, tuberculosis (TB) caused by the acid-fast bacilli, Mycobacterium tuberculosis (Mtb) is the most infectious killer disease globally with high morbidity and mortality rates. The rapid development of multi-drug-resistant (MDR) strains via intrinsic (efflux pumps) and acquired (biological mutations) mechanisms reduce the efficacy of applied anti-TB regimens. Nevertheless, only bedaquiline (BDQ) and pretomanid (PMD) were added to anti-TB therapy in the last decade. The existing anti-TB drugs also exhibited cytotoxicity and hepatotoxicity from long-term treatment. Thus, exploring or developing potential and less toxic anti-TB candidates, preferably natural-based candidates, is the call of the day. At present, 'quinoline' could be considered one of the versatile scaffolds presented in most mainstream medicines from comprehensive drug reports. Notably, BDQ with two clinically evaluating anti-TB candidates, TBJA-587 and DC-159a was motivated for utilizing quinoline heterocycles. Accordingly, we have selected 65 natural quinoline heterocycles bearing potential anti-TB agents (40 plant-derived and 25 marine-derived) within MIC value ≤ 50 μg/mL from an extensive literature search. Briefly, source, drug chemistry, structural activity relationship, prior pharmacokinetics profiles with drug-ability, toxicity, and hierarchical clustering analysis using various computational tools to identify the most 'drug-able lead' candidate is the uniqueness of the review. From extensive drug analysis, tetrandrine, 2'-nortiliacorinine, tiliacorine, globospiramine, evocarpine, allocuspareine from plant sources, and ecteinascidin 770, 6-hydroxymanzamine E, (-)-8-hydroxymanzamine A, ecteinascidin 786, manzamine F from marine sources are the most potential-cum-drug-able anti-TB candidates. We hope the systematic and critical drug analyses on quinoline-bearing natural anti-TB candidates are helpful to design potential-cum-less toxic anti-TB drugs in the future.