Synthesis of CC, CN coupled novel substituted dibutyl benzothiazepinone derivatives and evaluation of their thrombin inhibitory activity

C P Baburajeev; Chakrabhavi Dhananjaya Mohan; Vijay Pandey; Shobith Rangappa; Naveen Shivalingegowda; Leen Kalash; Sannaningaiah Devaraja; Andreas Bender; Peter E Lobie; Kanchugarakoppal S Rangappa; Basappa

doi:10.1016/j.bioorg.2019.03.004

Synthesis of CC, CN coupled novel substituted dibutyl benzothiazepinone derivatives and evaluation of their thrombin inhibitory activity

Bioorg Chem. 2019 Jun:87:142-154. doi: 10.1016/j.bioorg.2019.03.004. Epub 2019 Mar 5.

Affiliations

¹ Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
² Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
³ Tsinghua Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.
⁴ Adichunchanagiri Institute for Molecular Medicine, BG Nagara-571448, Nagamangala Taluk, Mandya District, India.
⁵ Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India.
⁶ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom.
⁷ Department of Studies and Research in Biochemistry, Tumkur University, Tumkur 572101, India.
⁸ Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: rangappaks@gmail.com.
⁹ Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India; Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: basappa.uom@gmail.com.

PMID: 30884308
DOI: 10.1016/j.bioorg.2019.03.004

Abstract

The formation of a thrombus is a key event in thromboembolic disorders, that contribute to high mortality and morbidity in affected patients. In the present study, we synthesized a library of novel substituted 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4(5H)-one derivatives which were tested for their platelet aggregation and thrombin inhibitory activity. Among the tested compounds, 3,3-dibutyl-7-(2-chlorophenyl)-8-methoxy-2,3-dihydrobenzo[b] [1,4]thiazepin-4(5H)-one (DCT) displayed the maximum thrombin inhibition with an IC₅₀ value of 3.85 μM and thus DCT was chosen for further studies. Next, the effect of DCT on primary hemostasis was evaluated using agonist-induced platelet aggregation model. The lead compound inhibited the collagen- or ADP- or thrombin-induced platelet aggregation in a dose-dependent manner. Furthermore, DCT prolonged the process of clot formation when evaluating plasma re-calcification time (320 ± 11 sec at 5 µg DCT), activated partial thromboplastin time (58.0 ± 0.01 sec at 2 µg), and prothrombin time (14.7 ± 0.01 sec at 5 µg). Molecular docking studies suggested that the benzothiazepinones evaluated here consistently display hydrogen bonding with Ser214 of thrombin, which is similar to that of the co-crystallized ligand (1-(2R)-2-amino-3-phenyl-propanoyl-N-(2,5dichlorophenyl)methylpyrrolidine-2-carboxamide). DCT displayed additional hydrogen bonding to Ser195 and π-π interactions between its methoxyphenyl groups and Trp60, thereby providing a structural rationale for the observed biological effect.

Keywords: Antiplatelet; Benzothiazepinone; Platelet aggregation; Thrombin inhibitor; Thromboembolic disorder.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation
Molecular Structure
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiazepines / chemical synthesis
Thiazepines / chemistry
Thiazepines / pharmacology*
Thrombin / antagonists & inhibitors*
Thrombin / metabolism

Substances

Serine Proteinase Inhibitors
Thiazepines
Thrombin