Probing the activity of BM212, an antimycobacterial, and its derivatives against multiple life cycle stages of Plasmodium falciparum

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Introduction The emergence of resistance to frontline antimalarial drugs underscores the urgent need for new chemotypes capable of targeting multiple P. falciparum life-cycle stages, including transmission stages. Methods Building on the antimycobacterial scaffold BM212 , we generated and profiled a focused library of 1,3,5-trisubstituted pyrroles to define the structural features driving activity against asexual blood-stage (ABS) parasites and late-stage gametocytes (LGc) of P. falciparum. Restults and Discussion Clear structure -activity relationship (SAR) trends emerged: the C3 cyclic amine was the dominant driver of life-cycle stage preference, with methylpiperazine substituent conferring potent gametocytocidal activity (compound 7, IC50 0.093 μM), whereas the dimethyl-azasilinane group enabled potent dual-stage profiles (compound 1 IC50 values 0.48 against LGc and 1.08 against ABS). At N1 and C5, electron-deficient aryl substituents (4-F-phenyl, 2-CF3-phenyl) consistently enhanced potency and improved physicochemical properties, while aliphatic rings (e.g., cyclobutyl) at N1 optimized hydrophobic fit and solubility. Specific combinations of these motifs yielded balanced dual-stage activity without compromising lipophilicity or metabolic stability. Several optimized analogues retained activity against the multidrug-resistant P. falciparum Dd2 strain, with IC50 values ranging from 1.01 to 1.54 μM and exhibited potent transmission-blocking activity, with compound 9 achieving 81% transmission-reducing activity in the standard membrane feeding assay (SMFA). Overall, this work positions BM212 -derived pyrroles as a promising and versatile multistage antiplasmodial chemotype, while delineating the key structural determinants required to achieve potency, selectivity, and transmission-blocking efficacy.

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