Evaluation of 2,3-Dihydro-1,5-benzothiazepine Derivatives as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies

Munirah M Al-Rooqi; Amina Sadiq; Rami J Obaid; Zaman Ashraf; Yasir Nazir; Rabab S Jassas; Nafeesa Naeem; Meshari A Alsharif; Syed Wadud Ali Shah; Ziad Moussa; Ehsan Ullah Mughal; Abdel-Rahman Farghaly; Saleh A Ahmed

doi:10.1021/acsomega.3c01566

Evaluation of 2,3-Dihydro-1,5-benzothiazepine Derivatives as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies

ACS Omega. 2023 May 4;8(19):17195-17208. doi: 10.1021/acsomega.3c01566. eCollection 2023 May 16.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
² Department of Chemistry, Govt. College Women University, Sialkot 51300, Pakistan.
³ Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.
⁴ Department of Chemistry, University of Sialkot, Sialkot 51300, Pakistan.
⁵ Department of Chemistry, Jamoum University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁶ Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan.
⁷ Department of Pharmacy, University of Malakand, Chakdara Dir 18000, Khyber Pakhtunkhwa, Pakistan.
⁸ Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, Abu Dhabi, United Arab Emirates.
⁹ Department of Chemistry, College of Science, Jazan University, Jazan 114, Saudi Arabia.

Abstract

Benzothiazepines are pharmacologically active compounds, frequently utilized as a precursor for acquiring versatile molecules with several bioactivities including anti-inflammatory, anti-human immunodeficiency virus (anti-HIV), analgesic, antitumor, antimicrobial, and antitubercular. In this study, the 2,4-diphenyl-2,3-dihydro-1,5-benzothiazepine scaffold was selected for their in vitro, docking, and druglikeness studies to evaluate their inhibitory potential against mushroom tyrosinase. All synthesized analogues, 1-14, exhibited moderate to good IC₅₀ values ranging from 1.21 to 70.65 μM. The synthesized benzothiazepine derivatives were potent tyrosinase inhibitors, which outperformed the reference kojic acid (IC₅₀ = 16.69 μM). The kinetic analysis revealed that compound 2 (2-(3,4-dimethoxyphenyl)-4-(p-tolyl)-2,3-dihydrobenzo[b][1,4]thiazepine) was a mixed-type tyrosinase inhibitor with a K_i value of 1.01 μM. Molecular modeling studies against tyrosinase protein (PDB ID: 2Y9X) were conducted to recognize the binding modes of these analogues. The utilization of molecular dynamic (MD) simulations enabled the assessment of the protein-ligand complex's dynamic behavior, stability, and binding affinity for the compounds. These simulations ultimately led to the identification of compound 2 as a potential inhibitor of tyrosinase. Additionally, a druglikeness study was conducted, which supported the promising potential of the new analogues as novel antityrosinase agents. The in silico studies were consistent with the in vitro results, showing that these ligands had good binding scores against tyrosinase and interacted with the core residues of the target protein. Gaussian 09 was used for the geometry optimization of all complexes.