Petasis-amide coupling enabled microwave-assisted synthesis of bis-benzothiazoles with safety profiling and...

A series of amide-linked bis-benzothiazoles was synthesized using an efficient microwave-assisted strategy that integrates the Petasis multicomponent reaction with HATU-mediated amide coupling. The methodology enabled rapid reactions (2 and 5 min) with high isolated yields of up to 94 %, highlighting the operational simplicity and energy efficiency of microwave-assisted organic synthesis. The structures of synthesized compounds were confirmed by FT-IR, ¹H and ¹³C NMR, and ESI-MS spectroscopy. In vitro safety profiling against J774.2 macrophages demonstrated low cytotoxicity for most derivatives (CC₅₀ > 200 µM). Antiprotozoal evaluation revealed notable activity against Leishmania mexicana, with compound 4a (IC₅₀ = 12.40 µM) and compound 5a (IC₅₀ = 27.05 µM) showing the highest potency, along with potent to good inhibition of Trypanosoma cruzi by compounds 5b and 5 g (IC₅₀ = 58.95 and 51.89 µM, respectively). Structure-activity relationship analysis indicated that electron-donating substituents (-CH₃, -OCH3) on the amide moiety reduced cytotoxicity while enhancing antiprotozoal activity. In particular, compounds 5a, 5b, and 5 g emerged as promising lead candidates with a favourable balance between potency and safety for further development as antiprotozoal agents.