Activity

Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 μM). selleck products Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer’s disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress.TUBERCULOSIS (TB) transmitted by Mycobacterium tuberculosis (Mtb) is one of the top 10 causes of death globally. Currently, the widespread occurrence of resistance toward Mtb strains is becoming a significant concern to public health. This scenario exaggerated the need for the discovery of novel targets and their inhibitors. Targeting the “Mtb cell wall peptidoglycan synthesis” is an attractive strategy to overcome drug resistance. Mur enzymes (MurA-MurF) play essential roles in the peptidoglycan synthesis by catalyzing the ligation of key amino acid residues to the stem peptide. These enzymes are unique and confined to the eubacteria and are absent in humans, representing potential targets for anti-tubercular drug discovery. Mtb Mur ligases with the same catalytic mechanism share conserved amino acid regions and structural features that can conceivably exploit for the designing of the inhibitors, which can simultaneously target more than one isoforms (MurC-MurF) of the enzyme. In light of these findings in the current review, we have discussed the recent advances in medicinal chemistry of Mtb Mur enzymes (MurA-MurF) and their inhibitors, offering attractive multi-targeted strategies to combat the problem of drug-resistant in M. tuberculosis.β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer’s disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.

Alcohol cessation improves mortality in alcohol-associated liver disease (ALD), but access to treatment is limited. To address this gap, implementation and early feasibility and outcomes of a multidisciplinary ALD clinic are described.

The clinic comprised a hepatologist, psychiatrist, psychologist, nurse, and social worker. Patients included those with alcohol-associated cirrhosis or acute alcoholic hepatitis who were not in the transplant evaluation process, who had less than 6 months’ sobriety and willingness to engage in alcohol use treatment. Psychosocial metrics in addition to routine hepatic function labs were collected. Treatment plans were tailored based on patient preferences and needs after multidisciplinary discussion.

89 patients were referred from both inpatient and outpatient settings, with 51 seen during the initial year. 38 remained active in clinic (4 died, 6 discharged, 3 moved to transplant clinic). 55% were women, 88% were white, 61% had private insurance. 49% had alcoholic hepatitis. 71% were decompensated. 80% had severe alcohol use disorder (AUD) and 84% had at least 1 comorbid psychiatric or substance use disorder. 63% chose one-on-one AUD treatment, 57% were prescribed relapse prevention medications. Mean MELD-Na score improved from baseline of 14 (SD 6.6) to 11.3 at 6 months (p=0.01). Hospital utilization significantly declined when comparing 6 months before to 6 months after initial visit (emergency department visits 0.51 to 0.20 per person-month; inpatient admission 0.34 to 0.14 per person-month; (β= -0.89, 95% CI -1.18 to -0.60).

A multidisciplinary ALD clinic was feasible with encouraging early outcomes. Further research should explore ways to expand this model and increase clinic capacity.

A multidisciplinary ALD clinic was feasible with encouraging early outcomes. Further research should explore ways to expand this model and increase clinic capacity.