Diflunisal-derived fluorinated biphenyl urea and carbamate derivatives with selective activity against Mycobacterium kansasii

Non-tuberculous mycobacterial infections remain difficult to treat because of limited therapeutic options. Herein, diflunisal (DIF) was utilised as a starting platform for the synthesis of novel lipophilic urea and carbamate derivatives. Key intermediate, methyl 4-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-carboxylate, was obtained by Suzuki–Miyaura cross-coupling and subsequently converted into 1,3-disubstituted ureas using isocyanates. Carbamates were prepared from the methyl ester of DIF and isocyanates under basic conditions. Evaluation against fast- and slow-growing mycobacteria, bacteria, and fungi showed a selective antimycobacterial profile. Urea derivatives showed potent activity against Mycobacterium kansasii , whereas activity against M. tuberculosis , M. smegmatis , M. aurum , bacterial pathogens, and fungi was generally marginal. Hexyl urea was the most active compound, inhibiting M. kansasii at 0.03 μg mL −1 (0.077 μM). The activity depended strongly on the nature and topology of the urea N -substituent. Carbamates did not exceed the highest activity observed in the urea series. No detectable cytostatic effect was observed for any of the target compounds in human MonoMac-6 and HepG2 cell lines up to 250 μM. These findings identify fluorinated biphenyl ureas as a previously unrecognised, highly selective chemotype for further investigation against M. kansasii .