Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties

Aya E Ghonim; Alessia Ligresti; Alessandro Rabbito; Ali Mokhtar Mahmoud; Vincenzo Di Marzo; Noha A Osman; Ashraf H Abadi

doi:10.1016/j.ejmech.2019.07.002

Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties

Eur J Med Chem. 2019 Oct 15:180:154-170. doi: 10.1016/j.ejmech.2019.07.002. Epub 2019 Jul 2.

Authors

Aya E Ghonim¹, Alessia Ligresti², Alessandro Rabbito², Ali Mokhtar Mahmoud², Vincenzo Di Marzo², Noha A Osman³, Ashraf H Abadi¹

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt.
² Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: noha.osman@guc.edu.eg.

PMID: 31302448
DOI: 10.1016/j.ejmech.2019.07.002

Abstract

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d]thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with K_is in the picomolar or low nanomolar range, and selectivity indices (K_i hCB1/K_i hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC₅₀s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model.

Keywords: Benzothiazole; CB2 agonists; CB2 ligands; DSS-Induced colitis; Structure-activity relationship; Thiazole.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Benzothiazoles / chemical synthesis
Benzothiazoles / chemistry
Benzothiazoles / pharmacology*
Cannabinoid Receptor Agonists / chemical synthesis
Cannabinoid Receptor Agonists / chemistry
Cannabinoid Receptor Agonists / pharmacology*
Colitis / chemically induced
Colitis / drug therapy*
Dextran Sulfate
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Male
Mice
Molecular Structure
Receptor, Cannabinoid, CB2 / agonists*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Benzothiazoles
Cannabinoid Receptor Agonists
Receptor, Cannabinoid, CB2
Thiazoles
Dextran Sulfate