Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton\u27s Tyrosine Kinase Inhibitors

Bruton\u27s tyrosine kinase (BTK) is a promising molecular target for several human B-cell-related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29 ± 0.52 µM), PID-6 (9.37 ± 2.47 µM), and PID-19 (2.64 ± 0.88 µM). These compounds caused a selective inhibition of Burkitt\u27s lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt\u27s lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics

Novel 5-Substituted Oxindoles Derivatives as Bruton\u27s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamic Simulation, and Biological Evaluation

Bruton\u27s tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by haemopoietic lineages, particularly B-cells. A new Oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modelling, docking, and ADME properties to select compounds. The Molecular dynamics simulation analysis carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562, and six non-BTK cancer cell lines, A549, HCT116 (parental and p53-/-), U2OS, JURKAT, and CCRF-CEM, and two non-malignant cell lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, which displayed potent activity against BTK-high RAMOS cells. These four compounds, each possessing free binding energies of -10.8, -11.1, -11.3, and -10.8 Kcal/mol, demonstrated antiproliferative and cytotoxic effects in RAMOS cells with IC50 values falling within the lower sub-micromolar range

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold naive tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQIVYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK- or Cys322-targeting drugs have a reduced potency to cause aggregation of naive tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK- or Cys322-targeting drugs may act as prophylactic agents against tau seeding.Web of Scienc

Evaluation of a diagnostic algorithm for sputum smear–negative pulmonary tuberculosis in HIV-infected adults

Background: The Revised National TB Control Program bases diagnosis of tuberculosis (TB) on sputum smear examination and response to a course of antibiotics, whereas World Health Organization recommends early chest radiography [chest x-ray (CXR)] for HIV-infected symptomatic patients. We evaluated the utility of initial CXR in the diagnostic algorithm for symptomatic HIV-infected patients with negative sputum smears. Methods: HIV-infected ambulatory patients with cough or fever of ≥2 weeks and 3 sputum smears negative for acid-fast bacilli were enrolled in Chennai and Pune, India, between 2007 and 2009. After a CXR and 2 sputum cultures, a course of broad-spectrum antibiotics was given and patients were reviewed after 14 days. Sensitivity, specificity, positive and negative predictive values of symptoms, CXR, and various combinations for diagnosing pulmonary tuberculosis (PTB) were determined, using sputum culture as gold standard. Results: Five hundred four patients (330 males; mean age: 35 years; median CD4: 175 cells per cubic millimeter) were enrolled. CXR had a sensitivity and specificity of 72% and 57%, respectively, with positive predictive value (PPV) of 21% and negative predictive value (NPV) of 93% to diagnose PTB. TB culture was positive in 49 of 235 patients (21%) with an abnormal initial CXR and 19 of 269 patients (7%) with a normal CXR (P < 0.001). Sensitivity and specificity of cough ≥2 weeks for predicting PTB was 97% and 6%, with PPV and NPV of 14% and 94%, respectively. Conclusions: Although moderately sensitive, basing a diagnosis of TB on initial CXR leads to overdiagnosis. An absence of weight loss had a high NPV, whereas none of the combinations had a good PPV. A rapid and accurate diagnostic test is required for HIV-infected chest symptomatic

Novel 5‑Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Bruton’s tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly B-cells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53–/–), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, possessing free binding energies of −10.8, −11.1, −11.3, and −10.8 kcal/mol, respectively, and displaying selective cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated the antiproliferative activity of 9h in RAMOS cells through selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk, upstream proteins in the BCR signaling pathway. In conclusion, we identified a promising oxindole derivative (9h) that shows specificity in modulating BTK signaling pathways