Human Group IIA secreted phospholipase A₂ (sPLA₂-IIA) enzyme plays a crucial role in several chronic inflammatory diseases such asasthma, atherosclerosis, gout, bronchitis, etc. Several studies showed that the antioxidants exert an anti-inflammatory function by inhibiting the sPLA₂-IIA enzyme. Hence, the present study evaluated an antioxidant molecule, sinapic acid, for sPLA₂-IIA inhibition as an anti-inflammatory function. Initially, the antioxidant efficacy of sinapic acid was evaluated, and it showed greater antioxidant potency. Further, sinapic acid inhibited 94.4 ± 4.83% of sPLA₂-IIA activity with an IC₅₀ value of 4.16 ± 0.13 µM. The mode of sPLA₂-IIA inhibition was examined by increasing the substrate concentration from 30 to 120nM and the calcium concentration from 2.5 to 15 mM, which did not change the level of inhibition. Further, sinapic acid altered the intrinsic fluorescence and distorted the far UltraViolet Circular Dichroism (UV-CD) spectra of the sPLA₂-IIA, indicating the direct enzyme-inhibitor interaction. Sinapic acid reduced the sPLA₂-IIA mediated hemolytic activity from 94 ± 2.19% to 12.35 ± 2.57% and mouse paw edema from 171.75 ± 2.2% to 114.8 ± 1.98%, demonstrating the anti-inflammatory efficiency of sinapic acid by in situ and in vivo methods, respectively. Finally, sinapic acid reduced the hemorrhagic effect of Vipera russelli venom hemorrhagic complex-I (VR-HC-I) as an anti-hemorrhagic function. Thus, the above experimental results revealed the sinapic acid potency to be an antioxidant, anti-inflammatory and anti-hemorrhagic molecule, and therefore, it appears to be a promising therapeutic agent.

New strategy for the synthesis of 2-(2,3,6,9-tetrahydro-1,3-dimethyl-2,6-dioxo-1H-purin-8-yl)acetonitrile through a molecular linking with pyridopyrimidine, pyrazolopyridine, and pyranonapthyridine derivatives. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, ¹H, ¹³C NMR, Mass spectral) analyses and further screened for their antimicrobial, antioxidant, and anticancer properties. Compound 6a indicated a higher activity against Gram-negative bacteria and compound 7d toward Gram-positive bacteria. Antifungal validation of the compounds revealed 7b as sensible against Aspergillus niger, Aspergillus oryzae, Candida albicans, and Penicillium chrysogenum at all concentrations. Compound 6b showed prominent cytotoxic activity with IC₅₀ (µM) values of 0.8 ± 0.61, 1.0 ± 0.3, 1.2 ± 0.7, and 0.90 ± 0.71 against MCF-7, A-549, HeLa, and Panc-1 cancer cell lines, respectively. Compounds 6c and 10c showed significant antioxidant activity at all concentrations with ED₅₀ values (3.39 ± 0.3 and 4.27 ± 0.5 μM, respectively). Further, docking was performed at the 1SA5 active site to anticipate their conceivable binding mode by compound 6b. Graphical Abstract

A series of novel triazolothiadiazolethione and triazolothiadiazine appended indolo[3,2-c]isoquinoline-5-one were designed, synthesized, and validated by IR, ¹H, ¹³C NMR, and mass spectroscopy strategies. All compounds are determined by their DFT investigations with B3LYP/def2-TZVP basis set level, ionization potentials, and electron affinities at vertical (IPv and EAv) and adiabatic parameters (IP_A and EA_A). Compound 3a has demonstrated the greatest values for these parameters. The compounds’ HOMO-LUMO (FMOs) and MEP maps were performed. The optimized structure of the compounds was estimated in global hardness, softness, global electrophilicity, and dipole moment. To find new drug candidates, different in vitro biological activities were implemented employing antimicrobial activity: Gram-negative bacteria were significantly suppressed by compound 4a, whereas gram-positive bacteria were strongly inhibited by compounds 3c and 3a has significant antifungal and anticancer effects. Compound 4b is profoundly antioxidant with IC₅₀ value of 8.74 ± 1.93 µg/mL and MIC value of 0.25 µg/mL for antituberculosis properties. Thereafter, all of the compounds were subjected to e-pharmacophore approach to molecular docking studies. Compound 4a exhibited the best docking score (−8.458 kcal/mol) and docking interactions with active binding sites of 1TL8 receptor.

A series of novel indolo[3,2-c]isoquinoline hybrids derivatives were synthesized. On the basis of spectroscopic and analytical data, the structures of newly synthesized compounds were determined. They were further evaluated for their in vitro antimicrobial, antioxidant anticancer and anti-TB activities. Results reveal that compounds 4a and 5a displayed better potency against all bacterial strains and compound 3b showed significant antifungal action against all fungi tested. Compound 4b display excellent antioxidant capability. Compounds 3a, 4a, and 5a bearing chloro on indolo[3,2-c]isoquinoline ring were found have higher potency against all cancer cell lines. Compound 5b displayed potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC 0.12 μg/mL. Consequently, a five-point e-pharmacophore model (AADDR) was built. Docking studies displayed that compounds 2a, 2b, 3a, 4b, and 4c exhibited stronger interactions and higher binding affinity toward Glu₁₆₆, Gln₁₈₉, and His₄₁, which are critical amino acid residues that play a significant role in PDB: 7D1M (SARS-CoV-2 M^pro) through hydrogen bonding, hydrophobic and π-π interactions. Further, frontier molecular orbitals studies were executed to understand their orbital energies and HOMO-LUMO lowest energy gap is 8.39 eV shown by compound 5a. Graphical Abstract

Poultry farm workers are highly susceptible to developing lung inflammatory diseases (asthma, COPD, ARDS, and ALI) due to prolonged exposure to organic dust and other airborne irritants in confined poultry facilities. Secretory phospholipase A2 (sPLA₂-IIA) is a vital proinflammatory enzyme play an important role in the production of inflammatory mediators. Hence, this study examined the regulatory role of secretory phospholipase A2 enzyme in poultry dust induced lung inflammation in in vitro and in vivo models. Lung epithelial A549 cells and BALB/c mice treated with poultry dust increased the sPLA₂-IIA mRNA expression and stimulated the induction of inflammatory symptoms. Inhibition of sPLA₂ enzyme activity by Tricyclic Dipyrido Diazepinone derivative 6 f (sPLA₂ inhibitor) markedly ameliorated ODE-induced lung histopathological conditions, decreased lung edema, cellular infiltration, and protein secretion. Further, downregulated activation of cPLA₂ via decreasing phosphorylation of ERK1/2 and p38. Suppressing cPLA₂ signalling cascade significantly reduced the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and chemokines (MIP-1, MCP, and RANTES). Consequently, the activation of COX-2 and the production of prostaglandin E2 and thromboxane B2 were significantly decreased. Conclusively, these findings indicated that sPLA₂-IIA could potentially serve as a novel therapeutic target for treating lung inflammation in disease conditions.