Discovery and evaluation of a 4-(benzothiazol-2-yl)-N-substituted aniline scaffold as MERS-CoV inhibitors.

Highly pathogenic coronaviruses pose a serious health threat. However, currently available small-molecule inhibitors (SMIs) targeting the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) spike (S) protein generally lack potency. Here, we design and synthesize a novel class of 4-(benzothiazol-2-yl)-N-substituted aniline derivatives. Distinct from most SMIs targeting viral enzymes, compound 22 potently inhibited both MERS-CoV pseudotyped and live viruses in vitro, with surface plasmon resonance (SPR) providing evidence for a direct interaction with the S protein. Alongside good solubility and metabolic stability, compound 22 exhibited in vivo proof-of-concept efficacy in hDPP4-transgenic mice by significantly reducing pulmonary viral loads. Overall, this study validates the 4-(benzothiazol-2-yl)-N-substituted aniline scaffold as an early anti-MERS-CoV pre-lead series, with compound 22 as a solid starting point for further optimization.