Synthesis of novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles by acid catalyzed intermolecular cyclization reactions of substituted dithiocarbazates as a possible 2019-nCoV main protease inhibitor

• Published in: Journal of molecular structure Vol. 1253; p. 132252
• Main Authors: Bhat, Muzzaffar A., Jan, Misba, Manzoor, Unjum, Shalla, Aabid H., Butcher, Ray J, Jasinski, Jerry P.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.04.2022
• Subjects: Cyclization; DFT; Dithiocarbazates; Docking; Thiadiazoles; Thiadiazoles; Dithiocarbazates; Docking; DFT; Cyclization
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.132252

•A convenient and facile synthesis of a privileged pharmaceutical scaffolds, 2,5-bis(substituted thio)−1,3,4-thiadiazoles is accomplished.•A simple procedure and high yields are the characteristic features of these reactions.•Compound 2b crystallizes in orthorhombic system with point group P bca.•Using the DFT/B3LYP/6–311 G (d,p) level of theory, HOMO-LUMO energy gap and molecular electrostatic potential (MEP) analyses were carried out.•The molecular docking studies of 2b-2e with 2019-nCoV main protease(7BRO) revealed binding free energies of (ΔGb) = −6.22, −5.38, −4.43 and −4.25 kcal mol−1 respectively. A convenient and facile synthesis of a privileged pharmaceutical scaffolds, 2,5-bis(substituted thio)-1,3,4-thiadiazoles is accomplished. The reaction of hydrazine hydrate with carbon disulfide and substituted alkyl/aryl chloride in basic medium yielded S-substituted alkyl/aryl dithiocarbazates in high yield. These dithiocarbazates on reaction with tetrafluoro acetic acid underwent a unique acid catalyzed intermolecular cyclization reaction to afford a novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles. A simple procedure and high yields are the characteristic features of these reactions. These compounds are characterized on the basis of physico-chemical and spectral (FT-IR, ESI Mass, 1H, 13C and DEPT 135° 13C {1H} NMR) studies. Compound 2b crystallizes in orthorhombic system with point group P bca. Using the DFT/B3LYP/6–311 G (d,p) level of theory, HOMO-LUMO energy gap and molecular electrostatic potential (MEP) analyses were carried out. The HOMO-LUMO energy gap allowed the calculation of chemical hardness, chemical inertness, electronegativity and the electrophilicity index of the molecule, which depicted their potential kinetic stability and reactivity. The molecular docking studies of 2b-2e with 2019-nCoV main protease(7BRO) revealed binding free energies of (ΔGb) = -6.22, -5.38, -4.43 and -4.25 kcal mol−1 respectively. Docking study revealed that the aromatic congeners exhibit appreciable therapeutic efficiency to be used as 2019-nCoV main protease inhibitors. [Display omitted]