POM analyses of antitrypanosomal activity of 2-iminobenzimidazoles: favorable and unfavorable parameters for drugs optim
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Med Chem Res (2013) 22:2437–2445 DOI 10.1007/s00044-012-0238-0
ORIGINAL RESEARCH
POM analyses of antitrypanosomal activity of 2-iminobenzimidazoles: favorable and unfavorable parameters for drugs optimization Taibi Ben Hadda • Rahima Mouhoub • Rahul Jawarkar • Vijay Masand • Ismail Warad
Received: 9 April 2012 / Accepted: 13 September 2012 / Published online: 26 September 2012 Ó Springer Science+Business Media New York 2012
Abstract POM virtual screening and docking of compounds 2-iminobenzimidazoles (IBIZ) as a novel class of trypanothione reductase inhibitors are described. These 2-IBIZ display potent trypanocidal activity against Trypanosoma brucei rhodesiense, with low cytotoxicity. A hypothetical mechanism based on bioinformatic analyses is proposed. The ligands with two neighbor pockets leading to bimetallic (M-Ligand-M/enzyme) complexes are more active than similar ligand without the two terminal arms. Keywords 2-Iminobenzimidazoles Trypanocidal activity Trypanosoma brucei rhodesiense Trypanothione reductase POM analyses
Introduction Parasitic protozoa of the family Trypanosomatidae are the causative agent of many significant tropical diseases
T. Ben Hadda (&) R. Mouhoub Laboratoire de Chimie des Mate´riaux, De´partement de Chimie, Faculte´ des Sciences d’Oujda, Universite´ Mohammed Premier, 60000 Oujda, Morocco e-mail: [email protected] R. Jawarkar Department of Pharmaceutical Chemistry, Sahyadri College of Pharmacy, Methawde, Sangola, Solapur, Maharashtra, India V. Masand Department of Chemistry, Vidya Bharati Mahavidyalaya, Camp, Amravati 444602, Maharashtra, India I. Warad Department of Chemistry, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
including African trypanosomiasis, Chagas disease, and Leishmaniasis. There are currently nine key drugs in use for the treatment of these disease states: suramin and pentamidine against early stage African trypanosomiasis and eflornithine and melarsoprol against late stage disease; nifurtimox (Nfx) and benznidazole (Bdz) against early stage Chagas disease; meglumine antimoniate and sodium stibogluconate against Leishmaniasis and amphotericin B against antimony-resistant strains. All of these drugs have severe limitations including long treatment regimes, lifethreatening side effects, varied efficacy against late stage diseases, and increasing incidence of drug resistance (Paulino et al., 2005; Sundar et al., 2000; Croft et al., 2006). Recently, Holloway et al. (2007) have analyzed various series by using a high-throughput screening campaign of a library of 100.000 lead-like compounds and identified 2-iminobenzimidazoles (IBIZ) (Fig. 1) as a novel class of trypanothione reductase inhibitors. These 2-IBIZ display potent trypanocidal activity against Trypanosoma brucei rhodesiense, which do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells.
Pharmacology Molecular properties calculations For compound 7 and certainly for its 2-IBIZ analogs bearing two functionalized arms, the c
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