2. Academic Validation
  3. Design, synthesis, QSAR modelling and molecular dynamic simulations of N-tosyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors

Design, synthesis, QSAR modelling and molecular dynamic simulations of N-tosyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors

  • Sci Rep. 2024 Oct 28;14(1):25754. doi: 10.1038/s41598-024-75100-1.
Zahra Batool 1,  Saeed Ullah 2,  Ajmal Khan 2 3,  Suraj N Mali 4,  Shailesh S Gurav 5,  Rahul D Jawarkar 6,  Abdulrahman Alshammari 7,  Norah A Albekairi 7,  Ahmed Al-Harrasi 8,  Zahid Shafiq 9
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan.
  • 2 Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, 616, Birkat Al Mauz, Nizwa, Sultanate of Oman.
  • 3 Department of Chemical and Biological Engineering, College of Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
  • 4 School of Pharmacy, D.Y. Patil University (Deemed to be University), Sector 7, Nerul, Navi Mumbai, 400706, India.
  • 5 Department of Chemistry, VIVA College, Virar, Maharashtra, 401303, India.
  • 6 Department of Medicinal Chemistry, Dr. Rajendra Gode Institute of Pharmacy, University-Mardi Road, Amravati, India.
  • 7 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, 11451, Riyadh, Saudi Arabia.
  • 8 Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, 616, Birkat Al Mauz, Nizwa, Sultanate of Oman. aharrasi@unizwa.edu.om.
  • 9 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan. zahidshafiq@bzu.edu.pk.
PMID: 39468115 DOI: 10.1038/s41598-024-75100-1
Abstract

Tyrosinase is an Enzyme crucial for the progression of melanogenesis. Immoderate production of melanin may be the cause of hyperpigmentation and darkening leading to skin diseases. Tyrosinase is the most researched target for suppressing melanogenesis since it catalyzes the rate-limiting stage of melanin production. Thiosemicarbazones have been reported to possess strong inhibition capability against Tyrosinase. We have designed and synthesized eighteen N-tosyl substituted indole-based thiosemicarbazones as competitive Tyrosinase inhibitors in the current work. All the compounds exhibited outstanding to good potency with half maximal inhibitory concentration in the range of 6.40 ± 0.21 µM to 61.84 ± 1.47 µM. The compound 5r displayed the top-tier inhibition amongst the entire series with IC50 = 6.40 ± 0.21 µM. Compounds, 5q and 5r exhibited competitive inhibitions in concentration dependent manner with Ki = 3.42 ± 0.03 and 10.25 ± 0.08 µM respectively. The binding mode of 5r was evaluated through in silico molecular dynamics simulations and molecular docking, while ADME assessment studies predicted the drug-like characteristics of the derivatives. The newly synthesized derivatives may serve as a structural guide for designing and developing novel Tyrosinase inhibitors.

Keywords

ADMET; DFT; Indole; Kinetics; Molecular docking; QSAR; Thiosemicarbazone; Tyrosinase.

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