New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1 '-Biphenyl]-4-carboxamido)benzoic acid derivatives

Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block humanto- mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1’- biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido) benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents.South African National Research Foundation; BMGF Grand Challenges Africa; South African Medical Research Council (SA MRC); South Carolina SmartState® Endowed Chair for Drug Discovery.https://chemistry-europe.onlinelibrary.wiley.com/journal/14397633am2023BiochemistryGeneticsMicrobiology and Plant PathologySchool of Health Systems and Public Health (SHSPH)UP Centre for Sustainable Malaria Control (UP CSMC

Slow-Binding Inhibition of <i>Mycobacterium tuberculosis</i> Shikimate Kinase by Manzamine Alkaloids

Tuberculosis represents a significant public health crisis. There is an urgent need for novel molecular scaffolds against this pathogen. We screened a small library of marine-derived compounds against shikimate kinase from <i>Mycobacterium tuberculosis</i> (<i>Mt</i>SK), a promising target for antitubercular drug development. Six manzamines previously shown to be active against <i>M. tuberculosis</i> were characterized as <i>Mt</i>SK inhibitors: manzamine A (<b>1</b>), 8-hydroxymanzamine A (<b>2</b>), manzamine E (<b>3</b>), manzamine F (<b>4</b>), 6-deoxymanzamine X (<b>5</b>), and 6-cyclohexamidomanzamine A (<b>6</b>). All six showed mixed noncompetitive inhibition of <i>Mt</i>SK. The lowest <i>K</i>_I values were obtained for <b>6</b> across all <i>Mt</i>SK–substrate complexes. Time-dependent analyses revealed two-step, slow-binding inhibition. The behavior of <b>1</b> was typical; initial formation of an enzyme–inhibitor complex (EI) obeyed an apparent <i>K</i>_I of ∼30 μM with forward (<i>k</i>₅) and reverse (<i>k</i>₆) rate constants for isomerization to an EI* complex of 0.18 and 0.08 min^–1, respectively. In contrast, <b>6</b> showed a lower <i>K</i>_I for the initial encounter complex (∼1.5 μM), substantially faster isomerization to EI* (<i>k</i>₅ = 0.91 min^–1), and slower back conversion of EI* to EI (<i>k</i>₆ = 0.04 min^–1). Thus, the overall inhibition constants, <i>K</i>_I*, for <b>1</b> and <b>6</b> were 10 and 0.06 μM, respectively. These findings were consistent with docking predictions of a favorable binding mode and a second, less tightly bound pose for <b>6</b> at <i>Mt</i>SK. Our results suggest that manzamines, in particular <b>6</b>, constitute a new scaffold from which drug candidates with novel mechanisms of action could be designed for the treatment of tuberculosis by targeting <i>Mt</i>SK