Design, Molecular Docking and In-Silico Analysis of Novel thiadiazole-azetidinone hybrids as Potential Antitubercular Agents

Abstract

The recent emergence of extensively drug-resistant tuberculosis has become a cause of concern for the management of tuberculosis globally. Shikimic acid pathway seems to be a potential and favorable target for the drug design of new anti-infective agents. This work aims to change the focus from traditional cell approaches to the target-based design of novel thiadiazolyl-azetidinone derivatives with Shikimate kinase as the drug target for anti-tubercular activity. Thiadiazole and azetidinone derivatives were methodically reprised to design a series of 3-chloro-4-(aryl)-1-(5-sulfanyl-1,3,4-thiadiazol-2-yl)azetidin-2-one derivatives (AZ1-AZ12). Molecular docking studies were performed on a crystal model of Mycobacterium tuberculosis Shikimate kinase (MtSK) using Vlife MDS 4.4 suite to evaluate their anti-tubercular potential. Further, drug-likeness properties and ADMET prediction were performed by molinspiration and admetSAR software to better describe the designed molecules as prospective candidates. 3-chloro-4-(4-nitrophenyl)-1-(5-sulfanyl-1,3,4-thiadiazol-2-yl)azetidin-2-one (AZ3), was found to be have better dock score when compared with the natural substrate, Shikimate. Docking studies confirmed that the molecules showed significant binding in the active site region of Shikimate kinase. Strong hydrogen bonding and hydrophobic interactions with amino acid residues and other parameters further explicate their effectiveness for inhibition of MtSK. Also, the physicochemical properties and drug scores for the designed compounds obtained by in silico studies were found to be satisfactory, signifying the overall potential of the designed molecules to be drug candidates. Thus these molecules could be explored as a lead for further anti-tubercular studies with Mycobacterium tuberculosis Shikimate kinase as the drug target.