TY - JOUR
T1 - Evaluation of 2,3-Dihydro-1,5-benzothiazepine Derivatives as Potential Tyrosinase Inhibitors
T2 - In Vitro and In Silico Studies
AU - Al-Rooqi, Munirah M.
AU - Sadiq, Amina
AU - Obaid, Rami J.
AU - Ashraf, Zaman
AU - Nazir, Yasir
AU - Jassas, Rabab S.
AU - Naeem, Nafeesa
AU - Alsharif, Meshari A.
AU - Shah, Syed Wadud Ali
AU - Moussa, Ziad
AU - Mughal, Ehsan Ullah
AU - Farghaly, Abdel Rahman
AU - Ahmed, Saleh A.
N1 - Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/5/16
Y1 - 2023/5/16
N2 - 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 Ki 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.
AB - 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 Ki 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.
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U2 - 10.1021/acsomega.3c01566
DO - 10.1021/acsomega.3c01566
M3 - Article
AN - SCOPUS:85159584185
SN - 2470-1343
VL - 8
SP - 17195
EP - 17208
JO - ACS Omega
JF - ACS Omega
IS - 19
ER -