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Synthesis, in vitro antiprotozoal activity, molecular docking and molecular dynamics studies of some new monocationic guanidinobenzimidazoles
Journal
European journal of medicinal chemistry
Volume
221
Pages / Article-Number
113545
Keywords
Antiparasitic activity; Molecular docking; Molecular dynamics; Monocationic guanidinobenzimidazoles; competing financial interests or personal relationships that could have appeared; to influence the work reported in this paper.
Mesh terms
Antiprotozoal Agents, pharmacology; Benzimidazoles, pharmacology; Cations, pharmacology; Dose-Response Relationship, Drug; Guanidine, pharmacology; Leishmania donovani, drug effects; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum, drug effects; Structure-Activity Relationship; Trypanosoma brucei rhodesiense, drug effects; Trypanosoma cruzi, drug effects
Abstract
A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.
