Current medicinal chemistry · 2026
Discovery of Furan-tethered Triazolothiadiazoles and Triazolothiadiazines as Potent Tyrosinase Inhibitors for the Treatment of Skin Diseases: Insights from Kinetics Data and Computational Modeling.
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Khan Majid, Ullah Atta, Halim Sobia Ahsan, Khan Imtiaz, Zaib Sumera, Hussian Humaira, Abdellattif Magda H, Jan Afnan, Ibrar Aliya, Khan Ajmal, Al-Harrasi Ahmed
Аннотация
INTRODUCTION: Tyrosinase, a copper-containing enzyme, is responsible for melanin production, and its overactivity can lead to hyperpigmentation.
METHODS: This study aimed to evaluate triazolothiadiazoles (3a-h, 4a-f) and triazolothiadiazines (5a-h) against human and mushroom tyrosinase isozymes.
RESULTS: Several derivatives, such as 3a-3b, 3d, 4c-4f, 5d, and 5e, were identified as potent and selective inhibitors of mushroom tyrosinase, with IC50 values ranging from 1.9 to 15.2 μM. Similarly, compounds 3f, 4b, 5a, and 5b effectively inhibited human tyrosinase, with IC50 values between 12.6 and 18.5 μM. Mechanism-based studies revealed that these active compounds exhibited competitive inhibition against both isozymes without any cytotoxic effects. In silico analysis further demonstrated that these compounds fit well into the active site of both tyrosinase isozymes.
CONCLUSION: Additionally, the pharmacokinetic profile of these compounds highlighted promising drug-like properties, making them potential candidates for the development of effective therapeutics for skin disorders.
METHODS: This study aimed to evaluate triazolothiadiazoles (3a-h, 4a-f) and triazolothiadiazines (5a-h) against human and mushroom tyrosinase isozymes.
RESULTS: Several derivatives, such as 3a-3b, 3d, 4c-4f, 5d, and 5e, were identified as potent and selective inhibitors of mushroom tyrosinase, with IC50 values ranging from 1.9 to 15.2 μM. Similarly, compounds 3f, 4b, 5a, and 5b effectively inhibited human tyrosinase, with IC50 values between 12.6 and 18.5 μM. Mechanism-based studies revealed that these active compounds exhibited competitive inhibition against both isozymes without any cytotoxic effects. In silico analysis further demonstrated that these compounds fit well into the active site of both tyrosinase isozymes.
CONCLUSION: Additionally, the pharmacokinetic profile of these compounds highlighted promising drug-like properties, making them potential candidates for the development of effective therapeutics for skin disorders.