Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation.

This study explores the pharmacological potential of chalcones through a multidisciplinary approach, including synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations. The synthesized compound, analyzed via single crystal X-ray diffraction, crystallized in the triclinic system (space group P-1) with C-H⋯O interactions stabilizing its structure. Hirshfeld surface analysis confirms these interactions, with H-H contacts dominating (45.1 %). Molecular electrostatics analysis reveals charge distribution, and a 3.10 eV HOMO-LUMO energy gap indicates bioactivity. Molecular docking identifies the compound (3a) showed a maximum Gscore of HTNF-α (-9.81 kcal/mol); Tubulin (-7.96 kcal/mol); COX2 (-7.88 kcal/mol), EGFR (-6.72 kcal/mol), and VEGFR1(-2.50 kcal/mol). Where compound (3c) showed maximum binding at the putative binding site with dock scores for VEGFR2 (-9.24 kcal/mol). This research not only advances molecular science but also holds promise for diverse applications, including drug design. The significance of this study lies in its comprehensive exploration of the pharmacological potential of chalcones using a multidisciplinary approach. Through the integration of synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations, we have extensively explored the structural and biochemical characteristics of these compounds. This investigation has revealed valuable insights that have the potential to lead to significant advancements in the fields of molecular science and drug design. Moreover, the molecular docking studies shed light on the compound's interaction with various biological targets. The significant binding affinities observed for these targets underscore the potential therapeutic relevance of the synthesized compound in diverse disease conditions.

Enantiomeric Separation of Indole-3-Propanamide Derivatives by Using Supercritical Fluid Chromatography on a Polysaccharide-Based Chiral Stationary Phase.

Thirteen pairs of I3P enantiomers were screened using nine polysaccharide chiral stationary phases and three different mobile phases. The purification strategy for 13 pairs of I3P enantiomers were designed and optimized considering enantiomeric purity and enrichment of isomers. Out of 13 I3P derivatives which were screened using supercritical fluid chromatography, 10 derivatives displayed excellent baseline separation using a Lux Cellulose-4 column and their resolution from higher to lower order of I3P-11, 13, 4, 12, 2, 1, 9, 3, 7 and 8 derivatives whereas in case of Lux Cellulose-2 column, the moderate separation was achieved as compared to Cellulose-4 in the order I3P-5, 6 and 10 derivatives. Excellent enantiomeric separations and retentions for all 13 I3P enantiomer derivatives were obtained in Cellulose-4 and Cellulose-2 columns in presences of methanol as organic modifier without any additives except in the case of I3P 12 enantiomer. The absolute stereochemical assignment of the purified isomers was determined through an optical rotation study. Among the series of I3P derivatives, I3P-5 showed potent antioxidant activity against catalase with an IC50 value of 13.78 µM. Further molecular docking, MM/GBSA and molecular dynamics studies revealed that the I3P-5 derivatives effectively bind to catalase with a docking score of -5.41 kcal/mol. Which validated chiral docking and indicated great potential for enantiomeric separation in drug discovery and present studies (R)-enantiomer preferentially depicts good binding capacity with catalase.

Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

Venom peptides - A comprehensive translational perspective in pain management.

Venom peptides have been evolving complex therapeutic interventions that potently and selectively modulate a range of targets such as ion channels, receptors, and signaling pathways of physiological processes making it potential therapeutic. Several venom peptides were deduced in vivo for clinical development targeting pain management, diabetes, cardiovascular diseases, antimicrobial activity. Several contributions have been detailed for a clear perspective for a better understanding of venomous animals, their venom, and their pharmacological effects. Here we unravel and summarize the recent advances in wide venom peptides across varieties of species for their therapeutics prospects.

Synthesis, Characterization of 4-Anilino-6,7-Dimethoxy Quinazoline Derivatives as Potential Anti-Angiogenic Agents.

BACKGROUND: Quinazolines are a big family of heterocyclic compounds with anti-cancer properties. OBJECTIVE: The latest investigation was on synthesis, characterization of novel 4-anilinoquinazoline derivatives for their anti-angiogenic effect. METHOD: A series of novel 4-anilino-6,7-dimethoxy quinazoline derivatives were synthesized and characterized using 1H, 13C NMR, FT-IR and LC-MS techniques. Cytotoxicity assays were performed for all compounds against different cell lines such as Human colon carcinoma (HCT116), Human chronic myeloid leukemia (K562) and Human breast cancer (SKBR3) cell lines using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl tetrazolium Bromide (MTT), Trypan blue and Lactose dehydrogenase release assay. The selected compounds were evaluated for their anti-tumor and anti-angiogenic effect on EAC tumor model. The molecular docking studies were drawn using maestro 2D sketcher and energy minimize was compounded by OPLS 2005. RESULTS: Among all compounds, RB4 and RB7 showed moderate activity whereas RB1 showed most potent activity comparable with that of the standard drug cisplatin against all three cell lines. RB1 also inhibited the proliferation of tumor cells in three different cell lines. Further, in-vivo studies revealed that RB1 significantly reduced secretion of ascites, tumor cell proliferation and increased the life span of tumor bearing mice. The antiangiogenic effect of RB1 was revealed from the reduced vessel sprouting in the peritoneum region of treated mice and induced avascular zone in chorioallantoic membrane (CAM) model. The insilco molecular docking studies clearly demonstrate the dual inhibitory potential of RB1 against VEGFR-2 and EGFR from binding to the active site of its receptors. CONCLUSION: However these studies clearly show that RB1 might be a potent antitumor and anti-angiogenic agent representing a promising lead for further optimization and elucidation of the mechanism of action.

Exploring hemostatic and thrombolytic potential of heynein - A cysteine protease from Ervatamia heyneana latex.

ETHNOPHARMACOLOGICAL RELEVANCE: The latex of Ervatamia heyneana (Wall.) T. Cooke plant has been used for wound healing and various skin diseases by Indian tribes and folklore. AIM OF THE STUDY: To validate the scientific basis of heynein - a key protease of Ervatamia heyneana, in hemostasis and wound healing process. MATERIALS AND METHODS: The latex from E. heyneana was processed and subjected to two step purification. The purified heynein was assayed for proteolytic activity using casein as substrate and also attested by zymography. The inhibition studies confirmed the nature of heynein. Pure fibrinogen was used for fibrinogenolytic activity and citrated plasma was used for coagulant and fibrinolytic activities. The edema inducing action and hemorrhagic activity of heynein were assessed on mice model. RESULTS: The purified heynein exhibited proteolytic activity, which was confirmed by caseinolytic assay and zymography. The inhibition studies confirmed heynein to be a cysteine protease. Heynein showed complete hydrolysis of all the three subunits of human fibrinogen (Aα, Bß, γ). It exhibited strong pro-coagulant activity by reducing plasma clotting time from 248 to 39s at 40µg concentration. Heynein cleaved α polymer subunit in fibrin clot and did not induce edema and hemorrhage in mice models. The non-hemorrhagic nature was supported with histopathological studies of skin samples. CONCLUSION: Heynein displays strong pro-coagulant action associated with fibrin(ogen)olytic activity. This provides basis for the observed pharmacological action of Ervatamia heyneana and thereby justifies its use in folk medicine.

Synthesis, characterization and bioactivity studies of novel 1,3,4-oxadiazole small molecule that targets basic phospholipase A2 from Vipera russelli.

Secretory phospholipase A2 (sPLA2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC50 value of 11.52 µM. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the α-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.