Synthesis, Tyrosinase Inhibition, Molecular Docking, and DFT Studies of Amide Derivatives of Fexofenadine

Abstract

Tyrosinase is a core enzyme in the biosynthesis of melanin that is associated to dermatological illnesses, making its inhibition critical for cosmetics as well as therapeutic applications. To find new anti-browning and whitening agents, a series of twelve derivatives (1–12) of fexofenadine were prepared structurally deduced with the help of HR-ESIMS,¹H-, and ¹³C-NMR spectroscopy, and were screened for their in vitro tyrosinase inhibitory activity. All the synthesized products displayed excellent to moderate inhibitory activity except four compounds (1, 2, 6, and 9) which were found non-active compared with standard kojic acid (IC₅₀ = 16.9 ± 1.30 µM). Similarly, three compounds (7, 11, and 10) displayed excellent inhibitory activity having IC₅₀ values from 9.45 ± 0.7 to 12.61 ± 0.7 µM, better than standard. Furthermore, molecular docking study of the most active compounds (7, 10 and 11) recorded the highest docking score. Furthermore, by means of TD-DFT analysis a relationship between IC₅₀ values and the electronic properties of these compounds can be simulated, presenting a complex relationship where lower energy gap (Eg) values, along with suitable electronegativity (χ) and electrophilicity (ω) values, are indicative of increased biological potency. In the same manner, the physiochemical properties, drug likeness and ADMET studies of the investigated compounds gives us promising results, which might open new window for searching drug candidate in this class of compounds in near future.