Green and Regioselective Approach for the Synthesis of 3-Substituted Indole Based 1,2-Dihydropyridine and Azaxanthone Derivatives as a Potential Lead for SARS-CoV-2 and Delta Plus Mutant Virus: DFT and Docking Studies

Abstract

Great attempts have been done for the development of novel antiviral compounds against SAR-CoV-2 to end this pandemic situation and save human society. Herewith, we have synthesized 3-substituted indole/2-substituted pyrrole 1,2dihydropyridine and azaxanthone scaffolds using simple, commercially available starting materials in a one-pot, green, and regioselective manner. Further, the regioselectivity of product formation was confirmed by various studies such as controlled experiments, density functional theory (DFT), Mulliken atomic charge, and electrostatic potential (ESP) surface. In addition, 3substituted indole 1,2-dihydropyridine was successfully converted into a biologically enriched pharmacophore scaffold, viz., indolylimidazopyridinylbenzofuran scaffold, in excellent yield. Moreover, the synthesized 3-substituted indole 1,2-dihydropyridine/ 2-substituted pyrroles were analyzed in docking studies for anti-SARS-CoV-2 properties against their main protease (M pro ) and anti-Delta plus properties against their protein of the Delta plus K417N mutant. Further, the drug-likeness prediction was analyzed by the Lipinski rule and other pharmacokinetic properties like absorption, distribution, metabolism, excretion, and toxicity using preADMET prediction. Interestingly, the docking results show that out of 20 synthesized compounds, 5 of them for M pro of SAR-CoV-2 and 9 of them for 7NX7 spike glycoprotein's A chain of Delta plus K417N show greater binding affinity when compared with remdesivir that is the first to receive FDA approval and is currently used as a potent drug for the treatment of COVID-19. These results suggest that indole/pyrrole substituted 1,2-dihydropyridine derivatives are capable of combating SARS-CoV-2 and its Delta plus mutant.

A Comprehensive Update of Anti-COVID-19 Activity of Heterocyclic Compounds

“…A series of 3-substituted indole-based 1.2-dihydropyridine hybrids were synthesized by Jayabal et al, 95 and their inhibitory potential against SARS-CoV-2 was tested using a molecular docking approach. Out of the 20 prepared derivatives, compound 64 showed good binding affinity against the main protease (M pro ) (PDB code: 6LU7) of SARS-CoV-2 with a binding energy score of −8.6kcal/mol, as compared to the control drug remdesivir with a binding energy value of −7.7kcal/mol.…”

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2

“…In this section, representative examples of computationally predicted M pro SARS-CoV-2 inhibitors will be highlighted. Jayabal et al reported the synthesis of 3-substituted indoles 23 through a multi-component green synthetic approach via the reaction of nitroketene S , S -acetal, diamine-containing compound, 3-formylchromone, and indole in the presence of In(OTf) 3 as a catalyst in refluxing ethanol [ 62 ] ( Scheme 12 ). Computationally, some of the synthesized agents ( K1 – K6 ) showed inhibitory properties for SARS-COV-2 M pro (PDB: 6LU7) and spike glycoprotein (PDB: 7NX7) utilizing Auto Dock-Vina software (v. 1.1.2).…”

“…Computationally, some of the synthesized agents ( K1 – K6 ) showed inhibitory properties for SARS-COV-2 M pro (PDB: 6LU7) and spike glycoprotein (PDB: 7NX7) utilizing Auto Dock-Vina software (v. 1.1.2). For comparison, Remdesivir binding energy = −7.7, −6.5 kcal/mol is against main protease 6LU7 and spike glycoprotein 7NX7, respectively [ 62 ] ( Figure 23 and Figure 24 ).…”

“…Numerous waves of viral mutations were detected, potentially affecting transmissibility and severity in humans. Delta (B.1.617) and Delta plus (B.1.617.2) are deadlier and more infectious than the other mutations (for example, Alpha, B.1.1.7; Beta, B.1.351; or Gamma, P.1) [ 62 ]. Omicron is more extensively mutated and was detected in November 2021 with the viral wave spreading worldwide.…”

Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties

“…Several waves of SARS-CoV-2 mutants were observed, namely: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.427 and B.1.429), Eta (B.1.525), Iota (B.1.526), Kappa (B.1.617.1), Mu (B.1.621, B.1.621.1) and Zeta (P.2). The Omicron (B.1.1.529) variant was first identified in Botswana in Nov. 2021 and rapidly spread to all countries worldwide [ [9] , [10] , [11] , [12] ]. The Omicron variant is highly efficiently transmitted between humans.…”