Synthesis, characterization, enzyme inhibition and molecular docking studies of benzothiazole derivatives bearing alkyl phenyl ether fragments

Abstract

Novel benzothiazole derivatives containing alkyl/benzyl phenyl ether fragments have been synthesized through two step reaction process. Initially, 2-hydroxybenzaldehyde was refluxed with 2-aminothiophenol in the presence of sodium metabisulfite (Na2S2O5) in DMF solvent followed by treating it with alkyl and aromatic halides in the presence of triethylamine in dry acetone to get the product derivatives (1–11) in better yields. These products were characterized by means of modern spectroscopic (1H, 13C NMR and HR-ESI-MS) techniques and screened for in vitro tyrosinase inhibitory activity. In the series, three compounds 13 (IC50 = 8.6 ± 0.2 µM), 3 (IC50 = 11.1 ± 0.5 µM), and 12 (IC50 = 18.2 ± 0.1 µM) showed excellent inhibition comparing with the standard kojic acid (IC50 = 17.8 ± 0.6 µM). Likewise, six compounds 9, 10, 11, 2, 4, and 5 attributed significant activity ranging from IC50 22.6 ± 0.8 to 29.2 ± 0.3 µM. Besides, compound 6 (IC50 = 40.6 ± 0.5 µM) was found least active while two compounds 7 and 8 were found inactive. The molecular docking study on molecules and their interaction with tyrosinase protein revealed a consistent pattern in the activity of kojic acid. The electronic characteristics of active derivatives 2, 3, 9–12, and kojic acid were examined using the TD-DFT approach. The study found that the HOMO and LUMO were concentrated on the π-conjugated system of the benzothiazole rings moiety, indicating a significant delocalization of electrons. The study also found that compounds compared to kojic acid, possess chemical hardness and stability properties, with lower electrophilicity index indicating higher bioactivity and lower toxicity. The study also highlighted the importance of comprehensive ADMET profiling in early drug development to ensure safety and efficacy.