Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors

Devirammanahalli Mahadevaswamy Lokeshwari; Nanjappagowda Dharmappa Rekha; Bharath Srinivasan; Hamse Kameshwar Vivek; Ajay Kumar Kariyappa

doi:10.1016/j.bmcl.2017.05.059

Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H⁺/K⁺ ATPase inhibitors

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3048-3054. doi: 10.1016/j.bmcl.2017.05.059. Epub 2017 May 19.

Authors

Devirammanahalli Mahadevaswamy Lokeshwari¹, Nanjappagowda Dharmappa Rekha², Bharath Srinivasan³, Hamse Kameshwar Vivek⁴, Ajay Kumar Kariyappa⁵

Affiliations

¹ Department of Chemistry, Yuvaraja College, University of Mysore, Mysuru, India.
² Department of Biotechnology, JSS College for Arts, Commerce & Science, Mysuru, India.
³ Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ Sri Ram Chem, R & D Centre, Plot No 31, JCK Industrial Park, Belagola Industrial Area, Mysuru 570006, India.
⁵ Department of Chemistry, Yuvaraja College, University of Mysore, Mysuru, India. Electronic address: [email protected].

PMID: 28554871
DOI: 10.1016/j.bmcl.2017.05.059

Abstract

A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by ¹H NMR, ¹³C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H⁺/K⁺ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H⁺/K⁺ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs.

Keywords: 1-(Furan-2-yl)ethanone; Anti-inflammatory; Antidiabetic; Benzothiazepines; Chalcones.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Binding Sites
Chalcones / chemistry
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Furans / chemistry
Group II Phospholipases A2 / antagonists & inhibitors*
Group II Phospholipases A2 / metabolism
H(+)-K(+)-Exchanging ATPase / chemistry*
H(+)-K(+)-Exchanging ATPase / metabolism
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Molecular Conformation
Molecular Docking Simulation
Protein Structure, Tertiary
Proton Pump Inhibitors / chemical synthesis
Proton Pump Inhibitors / chemistry
Proton Pump Inhibitors / metabolism
Proton Pump Inhibitors / pharmacology
Thiazepines / chemical synthesis*
Thiazepines / chemistry
Thiazepines / metabolism
Thiazepines / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Chalcones
Enzyme Inhibitors
Furans
Proton Pump Inhibitors
Thiazepines
Group II Phospholipases A2
VRV-PL-VIIIa phospholipase A2, Vipera russelli
H(+)-K(+)-Exchanging ATPase
furan