Identifying inflammation-related targets of natural lactones using network pharmacology, molecular modeling and <i>in vitro</i> approaches

Natural lactones have been used in traditional and folklore medicine for centuries owing to their anti-inflammatory properties. The study uses a multifaceted approach to identify lead anti-inflammatory lactones from the SISTEMATX natural products database. The study analyzed the natural lactone database, revealing 18 lactones linked to inflammation targets. The primary targets were PTGES, PTGS1, COX-2, ALOX5 and IL1B. STX 12273 was the best hit, with the lowest binding energy and potential for inhibiting the COX-2 enzyme. The study suggested natural lactone, STX 12273, from the SISTEMATX database with anti-inflammatory potential and postulated its use for inflammation treatment or prevention. Communicated by Ramaswamy H. Sarma</p

Establishment of LCMS Based Platform for Discovery of Quorum Sensing Inhibitors: Signal Detection in <i>Pseudomonas aeruginosa</i> PAO1

Targeting the main three networking systems, <i>viz.</i> Las, RhI, and PQS, <i>via</i> natural quenchers is a new ray of hope for combating the persistent behavior of <i>Pseudomonas aeruginosa</i>. In the bacterial chemical vocabulary pyocyanin, N-AHLs and rhamnolipids are the main keywords, which are responsible for the social and nomadic behavior of <i>P. aeruginosa</i>. In the present work, LC-MS based real-time qualitative and quantitative analysis of pyocyanin, green phenazine, N-AHLs, and rhamnolipids were performed on <i>P. aeruginosa</i> PAO1. The quantitative analysis indicates that the production of pyocyanin and NHSLs increases with time while the production of rhamnolipids discontinued after 16 h. This indicates the emergence of persisters in the medium instead of planktonic cells. Rhamnolipids acting as a surfactant enhances the motility of the bacterial cells, whereas the pyocyanin is responsible for the biofilm formation. In a microtiter plate based assay, an effect of capsaicin and 6-gingerol was recorded. In the presence of capsaicin and 6-gingerol, a substantial decrease in the production of rhamnolipids, phenazine, quinolone, and N-AHLs was observed. Most interestingly, the 6-gingerol treatment led to a drastic decrease of rhamnolipids, phenazine, quinolone, and N-AHLs versus capsaicin. These studies demonstrate the effectiveness of the capsaicin and 6-gingerol on Las, PQS, and Rhl circuits in a bacterium in order to understand the persistent and social behavior. Here, we are reporting LC-MS/MS based qualitative and quantitative analysis of QS molecules by taking a low volume of culture (up to 200 μL). This method can be used as a platform to screen the new antivirulence agents for fighting the resistant behavior of <i>P. aeruginosa</i> during biofilm formation

Unveiling the healing properties of 2,3-dehydrosilychristin: a potential silymarin-derived flavonolignan from <i>Vitex negundo</i>

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans – silybin, silychristin and silydianin − 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin (7) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin (7) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.</p

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies