title: Exploration of rate-limiting conformational state for 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1'-biphenyl]-2-ols and N(omega)-oxides (tebuquine analogues) for antimalarial activity using molecular shape analysis and molecular field analysis studies.
abstract: Tebuquine is a 4-aminoquinoline that shows significantly more potency as an antimalarial than amodiaquine and chloroquine both in vitro and in vivo. To explore the conformation in the rate-limiting step and to elucidate pharmacophoric properties of tebuquine-related analogues, molecular shape analysis (MSA) along with molecular field analysis (MFA) methods were applied on a series of 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1'-biphenyl]-2-ol analogues and their Nomega-oxides possessing antimalarial activity. The study was performed using 45 compounds in which 37 molecules were taken as a training set for the derivation of the 3D quantitative structure-activity relationship models and eight molecules were kept as a test set to evaluate the predictive ability of the derived models. Both methods were analyzed in terms of their predictive abilities and produced comparable results with good conventional and cross-validated r2 values (0.908 and 0.886, respectively, for the MFA model and 0.846 and 0.812, respectively, for the MSA model). In external data set prediction, the MSA model scored much better than MFA. Steric, electrostatic, and hydrogen-bond donor/acceptor fields of molecules were found to be relevant descriptors for structure-activity relationships. The inclusion of polar solvent-accessible charged surface area and spatial descriptors in the MSA model generation resulted in a model with significant predictive ability for the test set molecules. This indicates the importance of the orientation of conformationally favored molecules inside the receptor site and solvation of the charged surfaces of the molecule by a polar solvent for the activity of the molecule. The results provided the appropriate tools for predicting the affinity of related compounds using a ligand-based approach, and for guiding the design and synthesis of novel and more potent antimalarial agents.
authors.affiliation: Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology (CSIR), Kolkata 700032, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Sharma
authors.forename: Sandeep
authors.initials: S
authors.lastname: Chhabra
authors.forename: Nitin
authors.initials: N
authors.lastname: Rai
authors.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D000655:Amodiaquine; C044651:tebuquine