Identification and development of novel indazole derivatives as potent bacterial peptidoglycan synthesis inhibitors

Background: Tuberculosis is well-known airborne disease caused by Mycobacterium tuberculosis. Available treatment regimen was unsuccessful in eradicating the deaths caused by the disease worldwide. Owing to the drawbacks such as prolonged treatment period, side effects, and drug tolerance, there resulted in patient noncompliance. In the current study, we attempted to develop inhibitors against unexplored key target glutamate racemase. Methods: Lead identification was done using thermal shift assay from in-house library; inhibitors were developed by lead derivatization technique and evaluated using various biological assays. Results: In indazole series, compounds 11 (6.32 ± 0.35 μM) and 22 (6.11 ± 0.51 μM) were found to be most promising potent inhibitors among all. These compounds also showed their inhibition on replicating and nonreplicating bacteria. Conclusion: We have developed the novel inhibitors against M. tuberculosis capable of inhibiting active and dormant bacteria, further optimization of inhibitor derivatives can results in better compounds for eradicating tuberculosis

Identification and development of oxoquinazoline derivatives as novel mycobacterial inhibitors targeting cell wall synthesis enzyme

Background: Tuberculosis (TB) still remains the leading cause of death worldwide and was unanswered till date. Available treatment strategies have many drawbacks such as longer treatment period, side effects, and drug interactions, which result in patient noncompliance. In the present work, we thrived to develop inhibitors against unexplored key target glutamate racemase. Methods: Lead was identified from in-house database using differential scanning fluorimetry, inhibitors were developed by lead derivatization technique and evaluated them by various biological assays. Results: In oxoquinazoline series, compounds 18 (10.1 ± 0.62 μM) and 22 (5.23 ± 0.34 μM) were found to be the most promising potent inhibitors among all. These compounds also showed their inhibition on replicating and nonreplicating bacteria. Conclusion: Our attempt to develop the potent novel inhibitors against Mycobacterium tuberculosis resulted in developing few promising inhibitors, yet these compounds need further studies to answer all questions in drug discovery. Further optimization of compounds can result in still better compounds for treating TB

Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro.

The content and organization of hyaluronan (HA) in the extracellular matrix (ECM) have been identified as strong indicators of inflammation in joint disease, although the source and role of HA as an effector of inflammation is not clear. In this study, we established co-cultures of activated human CD4 T cells with fibroblast-like synoviocytes (FLS) from osteoarthritis (OA) and rheumatoid arthritis (RA) subjects and examined the role of HA in promoting inflammatory events. Co-cultures of RA FLS with activated CD4 T cells generated an HA-enriched ECM that promoted enhanced monocyte adhesion compared to co-cultures of OA FLS with activated CD4 T cells. In addition, both OA FLS and RA FLS co-cultures with activated CD4 T cells elicited significant increases in the expression of IL1β, TNF, and IL6, with the increase in IL6 expression most prominent in RA co-cultures. Blocking HA synthesis and accumulation with 4-methylumbelliferone reduced expression of IL6, IL1β, and TNF in both OA FLS and RA FLS co-cultures. The increase in HA synthesis in the co-cultures was mimicked by IL6 trans-signaling of FLS in the absence of CD4 T cells. Inhibition of HA synthesis blocked the increase in IL6 by RA FLS mediated by IL6 trans-signaling, suggesting that the HA synthetic pathway may be a key mediator in IL6 expression by FLS. Overall, our study indicates that HA-enriched ECM generated by co-cultures of activated CD4 T cells with FLS from human joints creates a pathogenic microenvironment by promoting adhesion of leukocytes and expression of inflammatory cytokines including IL6