CoMFA and CoMSIA analysis of tetrahydroquinolines as potential antimalarial agents

• Published in: SAR and QSAR in environmental research Vol. 22; no. 5-6; pp. 473 - 488
• Main Authors: Deshpande, S., Jaiswal, S., Katti, S.B., Prabhakar, Y.S.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis Group 01-07-2011
• Subjects: 3D-QSAR; Animals; Antimalarials - chemistry; CoMFA; CoMSIA; Crystallography, X-Ray; Farnesyltranstransferase - antagonists & inhibitors; malaria; Models, Molecular; Pf-PFT inhibitors; Plasmodium falciparum; Quantitative Structure-Activity Relationship; Quinolines - chemistry; Rats; Static Electricity; tetrahydroquinolines
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2011.569945

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used on a dataset of compounds, some of them having been reported to inhibit Plasmodium falciparum protein, farnesyltransferase. The co-crystal structure of the lead molecule, BMS-214662 bound to Rat-PFT was used as a template. CoMFA yielded a good model, with
 = 0.909,
 = 0.617 and was validated using an external set (
 = 0.748). It compared favourably with CoMSIA. In the CoMFA model the steric and electrostatic fields exerted an almost equal influence on activity. The contour maps indicated the necessity for sterically large electropositive groups with electronegative tail to be present in these molecules for activity, and sterically large electronegative moieties on the sulfonamide linker. By incorporating these features some new compounds have been identified for further investigation.