title: First report on exploring structural requirements of 1,2,3,4- tetrahydroacridin-9(10H)-one analogs as antimalarials using multiple QSAR approaches: descriptor-based QSAR, CoMFA-CoMSIA 3DQSAR, HQSAR and G-QSAR approaches.
abstract: Due to the emergence of multidrug resistance of malaria parasites, there is an urgent need to modify existing antimalarial drugs through structural changes as well as to search new pharmacophores to counteract the induced resistance. In the present work, different quantitative structure-activity relationship (QSAR) models have been developed using a series of 73 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) analogs with well defined antimalarial activity against W2 clone to provide detailed insight into the main structural fragments that impart antimalarial activity to these molecules. To the best of our knowledge, this is first QSAR report of THA analogs as antimalarials. From the developed models, it may be inferred that for an enhancement in the antimalarial activity of the molecules: i) R2 position should be substituted with a bulky group (like phenyl, methoxy, isopropyl, tertiary butyl group) which may be further substituted with electrostatically favored positively charged group; ii) R3 position should be substituted with hydrophobically favored but sterically disfavored group; iii) R4 position should be substituted with positively charged group lacking any carbon atom and iv) R5 position should be substituted with two methyl groups. On the contrary, substitution with bulky group at R6 position may reduce the antimalarial activity. Using the developed models, we have designed and proposed some new compounds which showed good in silico predicted activity. The designed compounds may be experimentally proved to be active and useful THA derivatives as antimalarial compounds.
authors.affiliation: Drug Theoretics and Cheminformatics Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
authors.forename: Probir Kumar
authors.initials: PK
authors.lastname: Ojha
authors.forename: Kunal
authors.initials: K
authors.lastname: Roy
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008954:Models, Biological; D008958:Models, Molecular; D010961:Plasmodium / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000166:Acridines; D000962:Antimalarials