Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability. Eur J Pharm Sci. 2019 Jul 22;:105015 Authors: Guimarães DSM, de Sousa Luz LS, do Nascimento SB, Silva LR, de Miranda Martins NR, de Almeida HG, de Souza Reis V, Maluf SEC, Budu A, Marinho JA, Abramo C, Carmona AK, da Silva MG, da Silva GR, Kemmer VM, Butera AP, Ribeiro-Viana RM, Gazarini ML, Júnior CSN, Guimarães L, Dos Santos FV, de Castro WV, Viana GHR, de Brito CFA, de Pilla Varotti F Abstract The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to‑lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 μM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confoca...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research