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

Abstract

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. 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. 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.