Central Drug Research Institute

The ESX-5 secretion system in Mycobacterium tuberculosis exports PE/PPE virulence factors, with EccA5, an AAA+ ATPase, playing a pivotal role. We solved the crystal structure of EccA5's N-terminal TPR domain (EccA5NT) at 2.15 Å, revealing a monomeric fold with six TPR motifs and a variable β-finger. Biophysical studies, including SAXS and size exclusion chromatography, confirm its monomeric state. A flexible loop (residues 137-148) suggests dynamic substrate interactions. SPR, SAXS and in silico docking show moderate binding (KD = 3.43 μm) between EccA5NT's β-finger and EspG5's β2-β3 loop, indicating a role in PE/PPE-EspG5 complex disassembly. These findings elucidate the role of EccA5 in ESX-5-mediated secretion.

The 1H-NMR, LC-MS, and HPLC guided isolation of n-hexane and ethyl acetate fractions led to the purification of one new sesterterpene cheilanthenetetraol (1) together with thirteen known compounds (2-14) for the first time from Aleuritopteris bicolor Roxb. The structure of the isolated compounds were established by extensive analysis of spectroscopic data, 1D and 2D NMR, HR-ESI-MS, and IR. The isolated compounds (2, 3, 6, and 9-14), as well as the n-hexane, ethyl acetate fractions, and aqueous methanol extract, were evaluated for cytotoxic activity against the HepG2 cancer cell line. All the tested compounds exhibited significant cytotoxic activity with an IC50 ranging from 10.08 µM to 14.04 µM. The extracts exhibited moderate activity with an IC50 value of 315.68, 391.55, and 274.89µg/mL, respectively. The anti-inflammatory activity of compounds 6, 9, and 10 were assessed, and the results demonstrated that these compounds exhibited significant activity at 10 and 30 µM concentrations in LPS-stimulated macrophages.

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice.

Spiro-cyclobutanes are sp3-rich molecules with applications in synthetic chemistry and drug discovery. The existing literature focuses mainly on their synthesis via the metal-catalyzed functionalization of substrates, such as spiro-cyclobutenes. In this letter, we disclose a H-bond-directed photochemical synthesis of densely substituted spiro-cyclobutanes. Moreover, a strain-release- and H-bond-directed three-component reaction of alkenes, p-quinone methide, and NH4SCN is also discussed. The reaction outcome is explained through control experiments and DFT calculations.

Mycobacterium tuberculosis (Mtb) effectively suppresses host immunity to ensure its survival. We have earlier shown that the Acr1 protein of Mtb can inhibit the differentiation of dendritic cells (DCs). Consequently, in the current study, we examined the role of Acr1 in mitigating autoimmunity. Initially, we observed that Acr1 skews the differentiation of DCs into functionally competent myeloid-derived suppressor cells (MDSCAcr1) that chiefly secrete immunosuppressive molecules, expand regulatory T cells (TregAcr1) and attenuate inflammatory responses. Further, MDSCAcr1 suppress Th17 cells. Acr1 expanded MDSCs with a concurrent increase in myelin oligodendrocyte glycoprotein (MOG)-specific Tregs and a decline in Th17 cells in a murine experimental autoimmune encephalomyelitis (EAE) model and prevented the onset of the disease. These results were further validated in the prophylactic model of EAE. Mechanistically, Acr1 activates Tregs and MDSCs via the TLR-4 pathway, implicating innate immune recognition in Mtb-induced suppression. The results indicate a potential role of Acr1 against autoimmune diseases.

A practical and straightforward metal-free, one-pot protocol has been developed for the synthesis of 3-sulfenylimidazo[1,2-a]pyridines using the neutral ionic liquid [hmim]Br as both solvent and dual-function promoter. This efficient method integrates cyclocondensation and sulfenylation into a single operation, enabling simultaneous C–N and C–S bond formation without the need for transition-metal catalysts or external oxidants. The reaction proceeds smoothly with readily accessible 2-aminopyridine, phenacyl bromide, and arylsulfonyl chloride, latter being transformed in situ into a thiol equivalent under the same mild and neutral reaction conditions. The protocol also accommodates arylsulfonyl hydrazide and sodium aryl sulfinate as alternative sulfenylating agents. Overall, this one-pot sequential approach offers good functional-group tolerance, a broad substrate scope, avoids hazardous reagents, and aligns well with green chemistry principles through step economy and operational simplicity.