Design and synthesis of new 4-(2-nitrophenoxy)benzamide derivatives as potential antiviral agents: molecular modeling and in vitro antiviral screening (Electronic supplementary information (ESI) available: Appendix A. Supplementary data. See DOI: 10.1039/d1nj02710g)

Abdallah, Abdallah E.; Alesawy, Mohamed S.; Eissa, Sally I.; El-Fakharany, Esmail M.; Kalaba, Mohamed H.; Sharaf, Mohamed H.; Abo Shama, Noura M.; Mahmoud, Sara H.; Ahmed, Mostafa Al-Karmalawy Ahmed A.; Elkady, Hazem

Regarding the crucial role of deubiquitinase (DUB) enzymes in many viruses, in particular, Adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2, DUB inhibition was reported as an effective new approach to find new effective antiviral agents. In the present study, a new wave of 4-(2-nitrophenoxy)benzamide derivatives was designed and synthesized to fulfill the basic pharmacophoric features of DUB inhibitors. The molecular docking of the designed compounds against deubiquitinase enzymes of the aforementioned viruses was carried out. Significant molecular docking results directed us to conduct in vitro antiviral screening against the aforementioned viruses. The biological data showed very strong to strong antiviral activities with IC50 values ranging from 10.22 to 44.68 μM against Adenovirus, HSV-1, and coxsackievirus. Compounds 8c, 8d, 10b, and 8a were found to be the most potent against Adenovirus, HSV-1, coxsackievirus, and SAR-CoV-2, respectively. Also, the CC50 values of the examined compounds ranged from 72.93 to 120.50 μM. Finally, the in silico ADMET and toxicity studies demonstrated that the tested members have a good profile of drug-like properties. Furthermore, we concluded the structure–activity relationship (SAR) of the newly designed and synthesized compounds regarding their in vitro results, which may help medicinal chemists in further optimization to obtain more potential antiviral candidates in the near future as well.