Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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Topological and Physicochemical Characteristics of 1,2,3,4-Tetrahydroacridin- 9(10H)-Ones and Their Antimalarial Profiles: A Composite Insight to the Structure-Activity Relation§

Author(s): Brij K. Sharma, Saroj Verma, Yenamandra S. Prabhakar.

Abstract:

The study reports the QSAR rationales from multilateral approaches for the antimalarial activities (against W2 and TM90-C2B strains of Plasmodium falciparum) and physical properties (aqueous solubility, permeability and logD) of 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) derivatives. A modification to Free-Wilson matrix (parameter set) is introduced to improve the compound to parameter ratio of the analysis carried out in the study. The models from modified Free-Wilson and physicochemical parameters suggest that 5th (R1) and 8th (R4) positions of THA scaffold should be free from substitution for the antimalarial activity against both the strains. The THA’ s 6th (R2) and 7th (R3) positions’ substituents with a blend of hydrophobicity and polarity offer scope to modulate the activities of these compounds. The substituent group contributions derived here gives opportunity to examine various combinations possible from these analogues. The models from the topological and other structural indices has suggested that MLOGP, LP1 and JGI6 as three common important features for activity against W2 and TM90 strains. The topological indices participated in the models suggested a preference for longer path lengths in molecules for better activity against both strains. The PLS analysis of the descriptors identified in the feature selection approach, combinatorial protocol in multiple linear regression (CP-MLR), has suggested that MATS3e and nRORPh are best suited to modulate the W2 activity, and Me, T(S..F) and ARR are best suited to modulate the TM90 activity. In these derivatives the analysis of aqueous solubility, permeability and logD has suggested that most of the R1 and R4 substituents have contributed with same arithmetic sign to theses properties. For all other variations in these compounds, the permeability increased with increasing logD and decreased with increasing aqueous solubility. The results suggest ways for the activity-property modulation in these analogues.

Keywords: 1, 2, 3, 4-Tetrahydroacridin-9(10H)-ones, antimalarials, CP-MLR, modified Free-Wilson analysis, QSAR, topological descriptors.

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Article Details

VOLUME: 9
ISSUE: 3
Year: 2013
Page: [317 - 335]
Pages: 19
DOI: 10.2174/15734099113099990017
Price: $58