Síntese de derivados de di(2-piridil)piperazinas como potenciais agentes antimaláricos

Abstract

This work describes the planning, synthesis, and biological evaluation of a new series of di(2-pyridyl)piperazine derivatives, aiming to obtain effective agents against resistant strains of Plasmodium falciparum. The synthetic strategy adopted was based on the convergent construction of the heteroaromatic skeleton through Nucleophilic Aromatic Substitution (SNAr) reactions, employing sodium carbonate in DMF or propanol under heating (60 – 100°C). This step proved robust, providing nitrated intermediates with high yields, mainly ranging from 65 to 100%. For subsequent functionalization, the reduction of nitro groups was optimized using tin(II) chloride dihydrate (SnCl2.2H2O) in ethanol, a method that proved superior to classical catalytic hydrogenation in terms of cost-effectiveness and selectivity, achieving yields in the range of 61 to 84%. The final diversification of the compounds was carried out via amidation reactions, largely using EDC and HOBt coupling reagents (with yields ranging from 17 to 93%), the synthesis of the most promising analog (13b) required prior activation of the carboxylic acid to its corresponding acid chloride, isolated in 31% yield. Structure-Activity Relationship (SAR) analysis demonstrated that bioisosteric substitution of the original thiophene ring with furan or oxazole preserved antiparasitic activity, while the introduction of more polar heterocycles was important. The most significant advance, however, lay in the modification of the central ligand: the expansion of the six-membered piperazine ring to a seven-membered diazepam homopiperazine core resulted in the optimized candidate of the study. The 13b derivative, obtained via the acid chloride route, showed submicromolar potency (IC50 = 0,60 ± 0,05 µM) and an extremely high selectivity index (SI > 166), validating the hypothesis that the greater conformational flexibility conferred by the seven-membered ring favors antiparasitic activity.