The ongoing emergence of SARS-CoV-2 mutations underscores the urgent need for new antivirals that target key viral proteins. This study describes the design, synthesis, and evaluation of two series of 1,3,4-oxadiazole-tethered N-substituted isatin hybrids as inhibitors of the SARS-CoV-2 main protease (Mpro): 1,2,3-triazole-linked derivatives (9a–h) and pyrazole-linked derivatives (15a–d). Compounds 15a–c were identified as the most active derivatives in initial FRET-based screening. With an IC50 of 15.38 µM, 15c was the most effective inhibitor, as determined by subsequent enzymatic assays. 15a and 15b had IC50 values of 24.43 and 30.55 µM, respectively. The active chemicals inhibit Mprovia a noncompetitive/mixed mechanism (α = 0.41–0.44), at a KI value of 13.24 µM, according to enzyme kinetic studies. Additionally, the compounds exhibited favorable physicochemical and ADMET profiles and minimal cytotoxicity against normal IMR-90 cells. The stable predicted binding of the most active compound, 15c, within the Mpro active site was further supported by molecular docking and molecular dynamics simulations. Collectively, these findings identify 15c as the most active derivative in the present series and provide preliminary SAR insights that may guide further optimization of this scaffold as a potential class of SARS-CoV-2 Mpro inhibitors.
T. Al-Warhi, Md Sofequl Islam Mukim, Zainab M. Elsayed et al.· RSC Advances· 0 citations
Isocitrate dehydrogenase (IDH) enzymes convert isocitrate to α-ketoglutarate. When IDH1 or IDH2 is mutated, the enzyme gains a new function, and the oncometabolite D-2-hydroxyglutarate (D-2-HG) accumulates. Its epigenetic and metabolic effects depend on the tumor context. This review classifies mutant IDH inhibitors by chemical scaffold and relates their binding in the allosteric pocket to structure-activity trends, isoform selectivity, brain penetration, and clinical outcome. Mutant IDH1, mutant IDH2, pan-IDH, and covalent inhibitors are compared, with lessons from successful and failed clinical candidates. Resistance is treated separately: secondary mutations, isoform switching, metabolic adaptation, rational combinations, PROTAC degraders, and biomarkers. Since reduced 2-HG indicates target engagement rather than clinical benefit, design priorities for the next generation of IDH-directed agents are outlined.
Moataz A. Shaldam, Anwar A. El-Hamaky, Nourhan A. Khattab et al.· Drug Discovery Today· 0 citations
Background: Among natural products, vanillin (Van), a major component of Vanilla planifolia, exhibits multiple bioactivities, including antimicrobial effects. Methods: In this study, Van, its analogues o-vanillin (oVan), iso-vanillin (iVan), ethylvanillin (eVan), and a library of newly synthesized derivatives were evaluated against Helicobacter pylori strains with distinct antibiotic susceptibilities. Time-kill kinetics, antibacterial spectrum, and viability in a normal gastric cell line GES-1, were also assessed. Results: Van showed minimal or no activity (MIC and MBC > 128 µg/mL), whereas structural modifications markedly improved anti-H. pylori activity, with MIC values as low as 4 µg/mL. Compounds 16V, 20oV, and 29eV were among the most potent (MIC90 = 4–16 µg/mL). Activity depended on both the vanilloid core and substituent type. The compounds were inactive against representative Gram-negative and Gram-positive bacteria (MIC > 128 µg/mL). Selected compounds preserved viability in GES-1 cells. Hierarchical clustering, artificial neural clustering, and principal component analysis identified potency-related architectural motifs and strain-specific activity. Docking against H. pylori urease suggested that several compounds, particularly 16V, may interact with the enzyme, providing preliminary support for a possible involvement of this target. Conclusions: Systematic modification of the vanilloid scaffold generated selective and relatively non-cytotoxic anti-H. pylori hit compounds and confirmed the value of natural metabolites in antibacterial drug discovery.
Ilaria D’Agostino, Strahinja Z. Kovačević, Moataz A. Shaldam et al.· Antibiotics· 0 citations
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