Sajda Ashraf

Introduction/Objective: Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disorder whose reproductive, metabolic, and inflammatory features are not adequately addressed by existing single-mechanism therapies. A1, a novel 7-azaindole derivative (1-methyl -4- {1H-pyrrol [2,3-b] pyridine-3-yl-1, 2, 3, 6-tetrahydropyridine), was selected based on its structural resemblance to melatonin, which has been reported to possess antidiabetic properties. This study evaluated the reproductive, hormonal, and glycemic effects of A1 for the treatment of PCOS in a rat model. Methods: Sixty virgin female Albino Wistar rats (n=15/group across four groups: control, negative control/PCOS, standard [metformin], and A1-treated) were induced with PCOS by administering oral letrozole and were treated with A1 for 30 days. A subset of animals (n=3/group) received extended treatment for 60 days to assess subchronic toxicity. Evaluations included ovarian histopathology, hormonal assays, glycemic parameters, lipid profiling, cytotoxicity assays, molecular docking, and gene expression analysis. Results: A1 treatment eliminated ovarian cysts, restored estrous cyclicity (89.36% by day 21-28, versus 0% in the PCOS group), improved lipid profiles, and restored hormonal profiles (reducing testosterone, LH, and estradiol while increasing FSH and SHBG toward control values; p<0.01). A1 exhibited alpha-glucosidase inhibitory activity (63.45% inhibition; IC50 88±5.7 μM) and antioxidant activity (83.25% DPPH scavenging at 100 μg/ml). However, extended administration was associated with histological changes in the liver and kidney suggestive of potential hepatic and renal stress, which warrants confirmation with biochemical toxicity markers. Discussion: A1's therapeutic effects likely reflect combined hormonal restoration and glucose-lowering activity consistent with its structural resemblance to melatonin, while the predicted FSHR interaction identified by molecular docking remains a computational hypothesis that has not yet been functionally validated. The hepatic and renal histological changes observed after extended dosing, together with the absence of biochemical toxicity markers and in vivo pharmacokinetic data, indicate that further structural optimization and toxicological characterization are needed before A1 can be considered for clinical development. Conclusion: A1 significantly restored endocrine and hormonal markers, glucose, insulin, and dyslipidemia while enhancing FSHR gene expression; molecular docking predicted binding within the FSHR allosteric pocket, a finding not yet functionally validated. These results indicate that A1, a novel 7-azaindole derivative, may regulate reproductive and metabolic dysfunctions in PCOS through endocrine modulation and receptor-- mediated mechanisms, demonstrating significant therapeutic potential for PCOS and ameliorating key metabolic and endocrine disturbances. While promising, its toxicity profile warrants further structural optimization for clinical development.

Background: Sarcopenia is an aging-related syndrome characterized by loss of skeletal muscle mass, strength, and function, with no approved pharmacological treatment. This study aimed to design, synthesize, and evaluate novel ML-167 derivatives for sarcopenia-associated muscle wasting. Methods: ML-167 derivatives were synthesized and characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Biological activity was evaluated in C2C12 myoblasts using MTT and Western blot assays. Selected compounds were evaluated in a dexamethasone-induced muscle wasting model. Muscle strength, mass, biochemical parameters, and histopathology were assessed. Structure–activity relationships were analysed using cell viability, molecular docking, and ligand efficiency data, alongside physicochemical properties. Results: Compounds 6b (116%), 3a (115%), 8d (114%), 4c (112%), 3m (112%), and 3c (111%) showed the highest C2C12 viability at 1 μM. Compounds 3a, 3c, and 6b increased MyH3 expression by approximately 1.6–1.7-fold, while MyoG remained near basal levels. In vivo, these compounds improved muscle strength, mass, and biochemical parameters without overt hepatic or renal abnormalities based on assessed serum and histopathological findings. Among the evaluated derivatives, compound 6b emerged as the most promising overall lead candidate, showing the greatest improvement in skeletal muscle mass and metabolic parameters, whereas compound 3c demonstrated the strongest histopathological protection and favourable effects on muscle strength with favourable physicochemical properties. Molecular docking supported the SAR trends, although did not consistently correlate with cellular activity. Conclusions: The findings identify 3a, 3c, and 6b as promising lead compounds and support further investigation of ML-167 derivatives as potential pharmacological approaches for sarcopenia-associated muscle wasting.

Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in pathogen-mediated lung inflammation. Viral-induced cytokine release syndrome (CRS) has emerged as a global pandemic, characterized by a hyperactive immune response and excessive cytokine production causing irreversible lung injury. This study aimed to evaluate FDA-approved drugs for their potential to target hyperactive immune response and SARS-CoV-2 viral replication simultaneously. Six potential 3-CL^pro inhibitors were identified by molecular docking using MOE software, including ebastine (1), orlistat (2), atracurium besylate (3), piperaquine phosphate (4), valsartan (5), and acarbose (6), among which 1–3 binds strongly to the target protein with binding affinity of − 8.22, − 9.12, and − 7.81, kcal/mol, respectively. Additionally, all identified inhibitors except 4 revealed significant anti-viral potential, with a 50–100% reduction in SARS-CoV-2 plaques. Significant attenuation of phagocyte oxidative burst and inflammatory cytokines (IFN-γ, GM-CSF, IL-6, IL-2, IL-1β, TNF-α) demonstrated the immunomodulatory potential of these drugs. This study demonstrates the potential of pre-existing drugs to ameliorate the cytokine storm and oxidative damage with simultaneous anti-viral effects. The data provide pre-clinical support to develop these drugs as potential therapeutic agent against ARDS.

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC₅₀ values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.

Cyclin-dependent kinase 2 (CDK2) is a key mediator of multiple oncogenic signalling pathways. Its activity is crucial for loss of proliferative control during tumorigenesis1. Initial interest in dr...

The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16–24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains.