New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors

Abstract

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by ¹H NMR,¹³C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship.

Communicated by Ramaswamy H. Sarma

Keywords:

• Carbonic anhydrase I
• carbonic anhydrase II
• acetylcholinesterase
• 1,3,4-Thiadiazole derivatives
• molecular docking
• molecular dynamic simulations

Acknowledgments

We would like to thank MERLAB and BİBAM, Anadolu University for spectral analysis.

Author contributions

Drug design: S.D. and A.E.E., chemical synthesis: S.D., chemical analysis: S.D. and D.N., in vitro enzyme tests: C.T., Y.D. and Ş.B., molecular docking & Molecular dynamic simulations: A.E.E, DFT calculations: D.N., analysis and evaluation of the results: L.Y. and Ş.B., article’s writer: L.Y., Ş.B., A.E.E., D.N., S.D., C.T. and Y.D., article review: L.Y., S.D., A.E.E. and D.N.

Disclosure statement

The author confirms that this article content has no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.