Synthesis, antimalarial, antiproliferative, and apoptotic activities of benzimidazole-5-carboxamide derivatives

Twenty-eight compounds of the type N´-substituted-2-(5-nitroheterocyclic-2-yl)-3H-benzo[d]imidazole-5-carboxamide were obtained using as an oxidizing agent the nitrobenzene to obtain the benzimidazole scaffold, a modification of the Steglich esterification reaction was used to obtain the final compounds. The compounds were tested as potential inhibitors of the β-hematin formation in vitro, and in vivo were tested as antimalarial against mice infected by a strain of Plasmodium berghei ANKA sensitive to chloroquine. The survival time was increased by the compounds 3a and 4d to 17.00 ± 1.26 and 20.20 ± 1.95 days, while the progress of the infection was reduced to 4.02 ± 0.45 and 3.05 ± 0.09, respectively. The cytotoxic activity of all these compounds was assessed against Jurkat E6.1 and HL60 two human cancer cell line, and fresh human lymphocytes. Four compounds 4a, n and 5a, n showed enhanced cytotoxicity against Jurkat E6.1 and HL60 cell lines; fresh lymphocytes were not affected. Using flow cytometry, apoptotic cell death was observed at 24 h. The aforementioned compounds enhanced apoptosis both tumor cell lines decreasing cell survival by inhibiting autophagy.