3D-QSAR and Pharmacophoric study on 2,6-Disubstituted Thiazolo [4,5-b] Pyridines as H3 Receptor Antagonists

Histamine H receptor antagonist (HRA) is a promising therapeutic for CNS disorders including attention deficit hyperactivity disorder [ADHD], sleep disorders, epilepsy, schizophrenia and obesity. 2,6-Disubstituted thiazolo[4,5-b]pyridines reported for their H receptor antagonistic activity were selected for three dimensional quantitative structure activity relationship (3D-QSAR) and pharmacophoric study in order to establish structure activity relationship quantitatively and essential structural features. In the current study, VLife Molecular Design Suite software (VlifeMDS) was used for QSAR and biophore studies. Pharmagist (web based server) was used for pharmacophoric study. Partial least square regression (PLSR) analysis showed r= 0.7902, q=0.6449 and pred_r= 0.6650. In this model steric [S_138, S_826] and electrostatic descriptors [E_243, E_652] are involved to play an important role in eliciting biological activity. It showed good internal and external prediction. The contour plots provided further insight of the relationship between structural features of substituted thiazolo[4,5-b]pyridine derivatives and their activities which should be applicable to design newer potential HR inhibitors. In addition with these studies, pharmacophoric models were also produced using Molsign (VLifeMDS) and Pharmagist (web based server). The identified pharmacophore features are two aromatic and two hydrogen bond acceptor with Molsign whereas common pharmacophoric features with Pharmagist are two aromatic, two hydrophobic and four hydrogen bond acceptors. The present work may be useful for further lead optimization and designing of potent H receptor antagonists.