SYNTHESIS, ANTICANCER ACTIVITY, MOLECULAR DOCKING, AND ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION TOXICITY STUDIES OF NOVEL BENZOTHIAZINES

Abstract

ABSTRACT
Objective: A series of benzothiazine compounds were studied for absorption, distribution, metabolism, and excretion (ADME) properties to asses
their drug-like properties. Compounds 1-10 with favorable ADME properties were selected for molecular docking studies as PIM1 kinase inhibitors.
Methods: Synthesis of compound 1 and 7 by conventional heating and characterized by various methods. Molecular docking carried out using Glide
software; ADME toxicity predicted using QuickPro.
Results: Compound 1 showed a Glide score of −7.622 kcal/mol with good hydrophobic and hydrophilic interactions with PIM1 kinase proteins and
appears to be more potent. Structure-activity relationship study was made among the 10 compounds, and a basic template was arrived at. An analysis
of the structure - Affinity relationships suggested that the substituent at position three is important in influencing affinity.
Conclusion: Compounds with an alkyl spacer between the carboxyl group and the core benzothiazine ring are required for binding of the compounds
with the PIM1 kinase. It was further confirmed by its in vitro anticancer activity of compound 1 against K562 cell lines by 3-(4, 5dimethythiazol-2yl)-2,
5-diphenyl
tetrazolium
bromide
assay
by
exhibiting
an IC
50
value of 36.82 μg/ml.
Keywords: Benzothiazine, Molecular docking, Absorption; distribution; metabolism; and excretion properties, In vitro anticancer activity.