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

• Published in: JOURNAL OF MOLECULAR STRUCTURE
• Main Authors: Usman, Muhammad; Alam, Aftab; Zainab; Khan, Majid; Elhenawy, Ahmed A.; Ayaz, Muhammad; Alanazi, Mohammed M.; Latif, Abdul; Shah, Syed Adnan Ali; Ali, Mumtaz; Ahmad, Manzoor
• Format: Article
• Language: English
• Published: ELSEVIER 2025
• Subjects: Chemistry
• Online Access: https://www-webofscience-com.uitm.idm.oclc.org/wos/woscc/full-record/WOS:001290352800001
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.139504

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) 2 S 2 O 5 ) 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) 1 - 11 ) in better yields. These products were characterized by means of modern spectroscopic (1H, 1 H, 13 C NMR and HR-ESI-MS) techniques and screened for in vitro tyrosinase inhibitory activity. In the series, three compounds 13 (IC50 50 = 8.6 f 0.2 mu M), 3 (IC50 50 = 11.1 f 0.5 mu M), and 12 (IC50 50 = 18.2 f 0.1 mu M) showed excellent inhibition comparing with the standard kojic acid (IC50 50 = 17.8 f 0.6 mu M). Likewise, six compounds 9, 10, 11, 2, 4, and 5 attributed significant activity ranging from IC50 50 22.6 f 0.8 to 29.2 f 0.3 mu M. Besides, compound 6 (IC50 50 = 40.6 f 0.5 mu M) 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 it-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.