Anti-Tubercular Activity of Pyrazinamide Conjugates: Synthesis and Structure-Activity Relationship Studies.

Tuberculosis (TB) is an airborne infection caused by the bacteria Mycobacterium Tuberculosis (MTB). It mainly affects the lungs and causes severe coughing, fever, and chest pains. With the rising prevalence of drug-resistant and inactive Tuberculosis (TB), there is an essential need to discover more effective molecules capable of combating this heinous illness. Pyrazinamide is a first-line tuberculosis therapy that shortens prophylactic duration from twelve to six months. The majority of presently used tuberculosis medications were found by a mix of serendipity and innovative chemical alterations of an existing lead drug. Given that the majority of these discoveries occurred years ago, there is a definite need to use fresh methodologies and technology for discovery to meet the grave danger posed by tuberculosis and the rise of treatment resistance strains. Although current research has provided significant insight into TB transmission, diagnosis, and treatment in the last four years, much more progress is needed to successfully reduce tuberculosis prevalence and eventually eradicate it. The disease continues to be a public health concern, second only to HIV/AIDS in high fatality rates. This review focuses on current efforts to translate the anti-tubercular activity of all known pyrazinamide analogues and proposes a novel approach for developing new anti-tubercular drugs based on the fusion of pyrazinamide with various heterocyclic rings that shorten treatment for drug-sensitive and multidrug-resistant tuberculosis.

One-Pot Synthesis of Novel Hydrazono-1,3-Thiazolidin-4-One Derivatives as Anti-HIV and Anti-Tubercular Agents: Synthesis, Biological Evaluation, Molecular Modelling and Admet Studies.

BACKGROUND: The necessity for newer anti-HIV and anti-tubercular medications has arisen as a result of the prevalence of opportunistic infections caused by HIV (human immunodeficiency virus). OBJECTIVE: A series of ten new hydrazono 1,3-thiazolidin-4-one derivatives were synthesized in one-pot and evaluated for anti-HIV and anti-tubercular activities. Molecular Docking was accomplished with HIV-1 reverse transcriptase protein (PDB ID: 1REV) and Mycobacterium Tuberculosis (M. tuberculosis) H37Rv protein (PDB ID: 2YES) receptors along with drug-likeness and ADMET properties. METHODS: One-pot synthesis of hydrazono 1,3-thiazolidin-4-one derivatives was carried out by ketones, thiosemicarbazide and ethylchloroacetate with the catalyst of anhydrous sodium acetate. All the synthesized compounds were characterized and evaluated for their in-vitro anti-HIV and also evaluated for their in-vitro anti-tubercular activity against M. tuberculosis H37Rv. In-silico predicted physicochemical parameters were done by MedChem DesignerTM software version 5.5 and ADMET parameters by pkCSM online tool. Furthermore, molecular docking was performed with pyrx 0.8 by autodock vina software. RESULTS: All the synthesized compounds were characterized and evaluated for their in-vitro anti- HIV activity for inhibition of syncytia formation, which shows KTE1 with EC50 47.95 µM and Selectivity Index (SI) of >4.17 and for inhibition of p24 antigen production EC50 was found to be 80.02 µM and SI of >2.49. The compounds were also evaluated for their in-vitro anti-tubercular activity against M. tuberculosis H37Rv, in which KTE1 MIC values of 12.5µg/ml with SI of >4.0 and cytotoxicity against Vero cell lines. In-silico predicted physicochemical parameters for synthesized compounds which were found to be drug-like. Furthermore, docking has shown a good dock score and binding energy with anti-HIV and anti-tubercular receptors. CONCLUSION: From the novel synthesized molecules, none of the molecule is as effective as standards for anti-HIV and anti-tubercular drugs and hence can be further explored for its potential activities. Furthermore, derivatization was made to achieve more potent compounds for anti-HIV and anti-tubercular drugs.