Tuberculosis: An Update on Pathophysiology, Molecular Mechanisms of Drug Resistance, Newer Anti-TB Drugs, Treatment Regimens and Host- Directed Therapies.

Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.

Anticancer Activity and In Silico ADMET Properties of 2,4,5-Trisubstitutedthiazole Derivatives.

BACKGROUND: Recently, a series of 15 compounds with 2,4,5-trisubstitutedthiazole scaffold having 2- amino/amido/ureido functional groups attached with 5-aryl and 4-carboxylic acid/ester groups (1-15) were reported from our research group as novel potential inhibitors of carbonic anhydrase III (CA III) enzyme. Several research studies revealed the potential role of CA inhibitors as anticancer agents, giving us the impetus to further explore these compounds for their potential as anticancer agents. OBJECTIVES: The objective of this study is to investigate the potential of 2,4,5-trisubstitutedthiazole derivatives (1-15) for their possible cytotoxic activity (in vitro), and to calculate (in silico) the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties to evaluate the drug-likeness of these compounds. METHODS: Cytotoxic activity (in vitro) was carried out on two breast cancer cell lines (MCF7 and MDA231), and the lymphoblastoid human erythroleukemia cell line (K562) using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Doxorubicin was used as a positive control. ADMET properties were calculated (in silico) using the QikProp module of Schrodinger. RESULTS: Compounds 6 and 9 with a phenylureido group at 2-position, and a methyl-carboxylate moiety at 4-position having para-tolyl and benzyl moiety, respectively at the 5-position of the thiazole ring showed significant cytotoxicity against all the three cell lines. In particular, compound 6 with para-tolyl group at 5-position exhibited the most potent inhibitory effect on the viability of MCF7, MDA231 and K562 cells, with IC50 values of 22, 26 and 11 µM, respectively. Notably, all the highly active compounds possess a phenyluriedo group at 2-- position with a methyl ester group at 4-position, indicating the probable role of these substituents in the target interaction and inducing cytotoxicity. Interestingly, compounds 1-4 and 10-13 with a free amino group at 2-position did not show any cytotoxic effect on the K562 cell line, while exhibiting mild to moderate cytotoxicity against the MCF7 and MDA231 cell lines. However, none of the tested compounds showed any activity against normal human dermal fibroblast cells indicating the safety/tolerability of the examined concentrations. Furthermore, these compounds also exhibited satisfactory ADMET properties (in silico), without violating Lipinski's rule of five. CONCLUSION: The most active compounds 6 and 9 predicted to have good oral absorption and low human serum protein binding, exhibiting no reactive functional group and probable CNS activity compared with 95% of the known oral drugs as predicted (in silico) by QikProp. Thus, compounds 6 and 9 can be considered as lead molecules for further modification and discovery of novel anticancer agents with nanomolar potency.