Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents
| Autor: | Shweta Bhagat, Gourav Das, Minhajul Arfeen, Shabana I. Khan, Babu L. Tekwani, Mridula Ramkumar, Prasad V. Bharatam |
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| Rok vydání: | 2019 |
| Předmět: |
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Molecular Stereochemistry Plasmodium falciparum 01 natural sciences Biochemistry Antimalarials Structure-Activity Relationship chemistry.chemical_compound Parasitic Sensitivity Tests Drug Discovery Dihydrofolate reductase Moiety Antimalarial Agent Guanylthiourea Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Docking (molecular) Drug Design 4-Aminoquinoline Aminoquinolines biology.protein Pharmacophore |
| Zdroj: | Bioorganic Chemistry. 91:103094 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2019.103094 |
| Popis: | Guanylthiourea (GTU) has been identified as an important antifolate antimalarial pharmacophore unit, whereas, 4-amino quinolones are already known for antimalarial activity. In the present work molecules carrying 4-aminoquinoline and GTU moiety have been designed using molecular docking analysis with PfDHFR enzyme and heme unit. The docking results indicated that the necessary interactions (Asp54 and Ile14) and docking score (−9.63 to −7.36 kcal/mmol) were comparable to WR99210 (−9.89 kcal/mol). From these results nine molecules were selected for synthesis. In vitro analysis of these synthesized compounds reveal that out of the nine molecules, eight show antimalarial activity in the range of 0.61–7.55 μM for PfD6 strain and 0.43–8.04 μM for PfW2 strain. Further, molecular dynamics simulations were performed on the most active molecule to establish comparative binding interactions of these compounds and reference ligand with Plasmodium falciparum dihydrofolate reductase (PfDHFR). |
| Databáze: | OpenAIRE |
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