Synthesis of New 1,4-Dihydropyridine Scaffold Thiadiazole and Triazole Moiety and in silico Molecular Interaction Study of SARS-CoV-2 Mpro and ACE2 Protease

Background and Objective: In this work, the synthesis of 1,4-dihydropyridine based bioactive compounds for computational study with SARS-CoV-2 Mpro (PDB ID: 6y2f) and ACE2 (6M0J). Materials and Methods: A series of novel 1,4-dihydropyridine appended compounds (3a-3g and 4a-4g) were prepared through Hantzsch reaction and followed by amination method. The newly prepared compounds were satisfactorily analysed by CHN analysis and various spectroscopic (IR, 1 H NMR, 13C NMR and mass) tools. The compounds of remdesivir, hydroxychloroquine and CQ were optimized by Dmol3 Materials Studio software 2017. In silico study was executed to forecast binding efficiency of 3a-3g and 4a-4g with targeted receptor spike protein (host angiotensin-converting enzyme 2; ACE2; 6M0J) and SARS-CoV-2 main protease (6y2f). Results: The binding energy of the docked compounds (3a-3g), remdesivir, hydroxychloroquine and chloroquine was observed at -5.89, -6.74, -6.58, -6.38, -6.76, -5.83, -5.54, -4.40, -5.22 and -5.41 Kcal molG1 , respectively. The binding energies of the docked compounds (4a-4g), RDV, HQ and CQ were observed at -7.14, -6.62, -6.89, -6.60, -7.71, -6.55 and -6.52 Kcal molG1 , respectively. The results confirmed that the presence electron withdrawing groups on benzene such as nitro and chloro- substitutions or free benzene enhancement of the inhibitory behavior on SARS-CoV-2 Mpro. Conclusion: The present data of synthesized compounds 3a-3g and 4a-4g showed significant binding ability with this protease receptor and better than remdesivir (RDV), chloroquine (CQ) and hydroxychloroquine (HQ). Chloroquine (CQ) and compounds (3c), (4a), (4b), (4e) and (4f) exhibited good interaction with ACE2 receptor.