THE SELECTIVITY OF THE (3+2) CYCLOADDITION OF 1-BROMO-1-(ETHOXYCARBONYLMETHYLIDENE)- 2-NITROPHENYLHYDRAZINE TO 1-METHYL-4-PHENYL- 1,3-DIHYDRO-2<i>H</i>-1,5-BENZODIAZEPINE-2-THIONE AND THE BIOEVALUATION OF THE REACTION PRODUCTS

Abstract

We carried out comprehensive studies to elucidate the chemo- and regioselectivity of the cycloaddition reaction of 1-bromo-1-(ethoxycarbonylmethylidene)-2-nitrophenylhydrazine with 1-methyl-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thione. The electronic properties and mechanism of the reaction were systematically discussed using DFT/B3LYP/6-311G(d,p) level of theory. Reagents were screened to determine electrophilic/ nucleophilic reactivity, revealing that 1,5-benzodiazepine-2-thione is a nucleophile and 1-bromo-1-(ethoxycarbonylmethylidene)-2-nitrophenylhydrazine is an electrophile. The Parr function analyses indicated that the reactive site in 1,5-benzodiazepine-2-thione is the sulfur atom, and the C3 position of 1-bromo-1-(ethoxycarbonylmethylidene)-2-nitrophenylhydrazine was chosen as the primary reactive site, which is determined by a strong electron-deficient/electron-rich complementarity. These computational predictions supported the selectivity of the reaction. Transition states have been explored and kinetically most favorable pathway identified, exhibiting the lowest activation energy and modest entropic cost. As a result, spirocyclic compound was found to be the main product, which is consistent with kinetic control since any competing pathways had energy barriers that were high enough for formation efficiency to be partially inhibited. Among products tested, ethyl (Z)-5-(2-{[2-(methylamino)phenyl]imino}-2-phenylethylidene)-4-(4-nitrophenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate offers the most attractive overall toxicological profile, especially in relation to cardiac and environmental toxicity. Nevertheless, mutagenicity among all products is still the main barrier for further therapeutic application. Study of intermolecular interactions showing that H–H contacts (5.99–2.64 Å) are predominant (a predominance of H–H contacts accounting for 39.00% of all the interactions) was done using Hirshfeld surface analysis. These computational results matched those from experiments, confirming the theoretical model. Moreover, pharmacokinetic and physicochemical evaluations revealed that all the synthesized compounds had excellent absorption in the intestines, while the bioavailability and pharmacokinetic parameters were observed to be the most ideal. Taken together, the data highlight the antiviral potential for the tested compounds as candidates for therapeutic intervention against SARS-CoV-2.