In silico investigation of medicinal spectrum of imidazo-azines from the perspective of multitarget screening against malaria, tuberculosis and Chagas disease

• A library of 30 imidazo-azines and 10 selected tropical disease targets was investigated.
• Three tiers screening strategy was employed.
• Hit selection based on ligand efficiency and binding energy.
• Two compounds were selected as master keys against four receptors.

A chemical database of 30 representative imidazo-azines was built and screened against important tropical disease targets by computational docking. After three rounds of screening, an interaction profile was generated and analyzed. On the basis of binding energy and ligand efficiency, it was concluded that in general, imidazo-azine scaffold has a potential of being selective and simultaneous inhibitor against the five receptors Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7, Mt-pantothenate synthetase and Mt-thymidine monophosphate kinase. Interestingly, two compounds 2-(4-chlorophenyl)-N-cyclohexyl-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL011) and N-cyclohexyl-2-(4-methoxyphenyl)-6-methylH-imidazo[1,2-a]pyridine-3-amine (MCL017) showed highest binding energy against four targets namely Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7 and Mt-pantothenate synthetase. Eventually, in order to improve the decision making and success rate in actual efficacy evaluations other criteria such as lead-likeness were envisaged.

An extensive docking was performed using an in-house library of 30 imidazo-azines against 10 receptors. Two of the annulated azines viz., 2-(4-chlorophenyl)-N-cyclohexyl-6-methylHimidazo[1,2-a]pyridin-3-amine (MCL011) and N-cyclohexyl-2-(4-methoxyphenyl)-6-methylHimidazo[1,2-a]pyridin-3-amine (MCL017) were found to be the top scorers against four receptors Pf-dihydrofolate reductase, Pf-enoyl acyl carrier protein reductase, Pf-protein kinase 7 and Mt-pantothenate synthetase.Figure optionsDownload high-quality image (148 K)Download as PowerPoint slide