Synthesis, in vitro antiprotozoal activity, molecular docking and molecular dynamics studies of some new monocationic guanidinobenzimidazoles

DOĞANÇ F., ÇELİK İ., EREN G., Kaiser M., Brun R., GÖKER A. H.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.221, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 221
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.ejmech.2021.113545
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Antiparasitic activity, Molecular docking, Molecular dynamics, Monocationic guanidinobenzimidazoles, MINOR-GROOVE BINDERS, ANTIMICROBIAL ACTIVITY, DNA, BINDING
  • Ankara Üniversitesi Adresli: Evet

Özet

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. (C) 2021 Elsevier Masson SAS. All rights reserved.