Discovery of 2-aryl and 2-pyridinylbenzothiazoles endowed with antimicrobial and aryl hydrocarbon receptor agonistic activities

Benzothiazole is a privileged scaffold in medicinal chemistry present in diverse bioactive compounds with multiple pharmacological applications such as analgesic, anticonvulsant, antidiabetic, anti-inflammatory, an- ticancer and radioactive amyloidal imagining agents. We reported in this work the study of sixteen functiona- lized 2 -aryl and 2-pyridinylbenzothiazoles as antimicrobial agents and as aryl hydrocarbon receptor (AhR) modulators. The antimicrobial activity against Gram-positive (S. aureus and M. luteus ) and Gram-negative (P. aeruginosa, S. enterica and E. coli ) pathogens yielded MIC ranging from 3.13 to 50 mu g/mL and against the yeast C. albicans , the benzothiazoles displayed MIC from 12.5 to 100 mu g/mL. All compounds showed promising anti- biofilm activity against S. aureus and P. aeruginosa . The arylbenzothiazole 12 displayed the greatest biofilm eradication in S. aureus (74%) subsequently verified by fluorescence microscopy. The ability of benzothiazoles to modulate AhR expression was evaluated in a cell -based reporter gene assay. Six benzothiazoles (7, 8 - 10, 12, 13 ) induced a significant AhR-mediated transcription and interestingly compound 12 was also the strongest AhR- agonist identified. Structure -activity relationships are suggested herein for the AhR-agonism and antibiofilm activities. Furthermore, in silico predictions revealed a good ADMET profile and druglikeness for the ar- ylbenzothiazole 12 as well as binding similarities to AhR compared with the endogenous agonist FICZ.