Structural and stereochemical determinants for hGAT3 inhibition: development of novel conformationally constrained and substituted analogs of (S)-isoserine
AbstractThe GABA transporter 3 (GAT3) is a member of the GABA transporter (GAT) family proposed to have a role in regulating tonic inhibition. The GAT3-preferring substrate (S)-isoserine has shown beneficial effects in a mouse model of stroke accompanied by an increased GAT3 expression, indicating a molecular mechanism mediated by GAT3. However, (S)-isoserine is not ideally suited for in vivo studies due to a lack of selectivity and brain permeability. To elucidate the structural determinants of (S)-isoserine for GAT3 inhibition, and to optimize and inform further ligand development, we here present the design, synthesis a...
Source: Medicinal Chemistry Research - August 16, 2023 Category: Chemistry Source Type: research

Synthesis of indole-based ferulic acid derivatives and in vitro evaluation of antiviral activity against SARS-CoV-2
AbstractThe search for an effective small molecule against the severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) is a challenge that remains even after the end of the Coronavirus disease 2019 (COVID-19) global health emergency. The indole-based ferulic acid derivatives were synthesized in this work and evaluated for their in vitro cytotoxic profiles and anti-SARS-CoV-2 activity. Compounds1 and2 decreased the number of genomic copies of SARS-CoV-2 in a dose-dependent manner, with IC50 values of 70.85  µM and 68.28 µM, respectively, with no significant cytotoxicity up to 100 µM against uninfected ...
Source: Medicinal Chemistry Research - August 10, 2023 Category: Chemistry Source Type: research

A review of the synthesis, bioanalysis, and chemical reactivity of xenobiotic acyl-coenzyme a thioesters
AbstractIn this review, we describe current methodologies important for addressing the formation of xenobiotic acyl-coenzyme A-thioesters (acyl-CoAs). This includes the synthesis of reference standards of xenobiotic acyl-CoAs as an important tool in developing bioanalytical methods and for evaluating chemical reactivity. The review also describes current challenges and solutions for the LC-MS analysis of xenobiotic acyl-CoAs in biological samples. Reversed-phase chromatography is typically used, and the selection of mobile phases should be carefully considered. As acyl-CoAs are not excreted from cells and are thus not poss...
Source: Medicinal Chemistry Research - August 10, 2023 Category: Chemistry Source Type: research

Structure activity relationship (SAR) driven design and discovery of WCK 5107 (Zidebactam): novel β-lactam enhancer, potent against multidrug-resistant gram-negative pathogens
AbstractExtended-spectrum beta-lactamases (ESBL) are the enzymes responsible for producing multidrug-resistant (MDR) bacterial strains, making currently available β-lactam drugs ineffective against such bacterial infections. Avibactam and relebactam are the two non-β-lactam inhibitors approved in combination with other antibiotics for clinical use and originated from the diazabicyclooctane (DBO) series. However with time, ESBL strains produce a high degree of resistance, causing such drug combinations to be ineffectual. Under our program to explore an advanced candidate effective against ESBL-producing pathogens, we have...
Source: Medicinal Chemistry Research - August 9, 2023 Category: Chemistry Source Type: research

A review of the mechanisms of valproate-induced liver injury with an emphasis on the role of reactive metabolites discovered by Tom Baillie
AbstractThe anticonvulsant valproic acid (VA) is associated with a range of idiosyncratic drug reactions; the most common is liver injury. The liver injury can take several forms: hyperammonemia with encephalopathy, liver injury with hepatic microvesicular steatosis, liver injury without steatosis, and a Reye ’s-like syndrome. The most common form leading to liver failure is the injury with hepatic microvesicular steatosis. This is different from most drug-induced idiosyncratic liver injury. Children under the age of 2 and those with inborn errors in metabolism are at increased risk. VA is a simple bra nched carboxylic a...
Source: Medicinal Chemistry Research - August 7, 2023 Category: Chemistry Source Type: research

Synthesis of 2-amino-4H-chromenes catalyst-free via sequential Knoevenagel-Michael reaction and evaluation of biological activity in tumor cells
This study represents the first investigation into the biological activity of this compound class, offering a promising starting point developing of new antitumor agents. (Source: Medicinal Chemistry Research)
Source: Medicinal Chemistry Research - August 4, 2023 Category: Chemistry Source Type: research

Glutathione and glutathione disulfide – their biomedical and pharmaceutical applications
AbstractGlutathione (GSH) is an endogenous tripeptide (Glu-Cys-Gly) and the most abundant endogenous antioxidant. It protects the body against oxidative stress and reactive electrophiles. GSH and its oxidized form glutathione disulfide (GSSG) make up the most important thiol redox buffer in the body, and its homeostasis is critical to many important cellular functions. Dysfunction or disruption of the redox buffer has been implicated in various diseases and the implications make GSH, GSSG, and their related systems valid and effective targets for medicinal chemistry interventions. For example, increased levels of GSH and G...
Source: Medicinal Chemistry Research - July 28, 2023 Category: Chemistry Source Type: research

Synthesis of amide warhead containing coumarin derivatives as potential pancreatic lipase inhibitors: in silico and in vitro evaluation for obesity treatment
AbstractA series of coumarin-3-carboxamide analogues has been designed, synthesized and assessed for their ability to inhibit pancreatic lipase (PL). Amongst all the synthesized analogues5q,5k and 5c exhibited potential PL inhibition activity with IC50 values of 19.41, 21.30 and 24.90  µM, respectively when compared to orlistat (IC50 = 0.97 µM). Analogue5q was found to inhibit PL with IC50 value of 19.41  µM and in a competitive manner with an inhibition constant (Ki) of 10.386  µM. Further, the docking study confirmed the interaction of analogue5q (MolDock score of −113.845 kcal mol−1) with importa...
Source: Medicinal Chemistry Research - July 28, 2023 Category: Chemistry Source Type: research

Glutathione and glutathione disulfide – their biomedical and pharmaceutical applications
AbstractGlutathione (GSH) is an endogenous tripeptide (Glu-Cys-Gly) and the most abundant endogenous antioxidant. It protects the body against oxidative stress and reactive electrophiles. GSH and its oxidized form glutathione disulfide (GSSG) make up the most important thiol redox buffer in the body, and its homeostasis is critical to many important cellular functions. Dysfunction or disruption of the redox buffer has been implicated in various diseases and the implications make GSH, GSSG, and their related systems valid and effective targets for medicinal chemistry interventions. For example, increased levels of GSH and G...
Source: Medicinal Chemistry Research - July 28, 2023 Category: Chemistry Source Type: research

Synthesis of amide warhead containing coumarin derivatives as potential pancreatic lipase inhibitors: in silico and in vitro evaluation for obesity treatment
AbstractA series of coumarin-3-carboxamide analogues has been designed, synthesized and assessed for their ability to inhibit pancreatic lipase (PL). Amongst all the synthesized analogues5q,5k and 5c exhibited potential PL inhibition activity with IC50 values of 19.41, 21.30 and 24.90  µM, respectively when compared to orlistat (IC50 = 0.97 µM). Analogue5q was found to inhibit PL with IC50 value of 19.41  µM and in a competitive manner with an inhibition constant (Ki) of 10.386  µM. Further, the docking study confirmed the interaction of analogue5q (MolDock score of −113.845 kcal mol−1) with importa...
Source: Medicinal Chemistry Research - July 28, 2023 Category: Chemistry Source Type: research

Using molecular networking and docking to explore arginase inhibitors among Drimys brasiliensis chemical constituents
This study has investigated whether the bark and leaves ofDrimys brasiliensis Miers (Winteraceae), a plant known for its antileishmanial effect, can inhibitLeishmania amazonensis arginase. IC50 values of 13.6 and 8.0  μg/mL were obtained for the ethanolic extracts fromD. brasiliensis bark and leaves, respectively. Liquid chromatography –high resolution mass spectrometry analysis of the bioactive extracts helped to identify ten compounds, including flavonoids, phenolic acids, and hydroxycinnamic acid derivatives. Among these compounds, flavonoids and chlorogenic acid are known for potentially inhibiting arginase, and t...
Source: Medicinal Chemistry Research - July 24, 2023 Category: Chemistry Source Type: research

Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans
In this study, a series of deguelin (Deg) derivative were prepared and identified with in vitro antifungal activity against drug-resistantC. albicans combined with fluconazole (FLC). The combination of Deg derivative17c and FLC exhibited the best activity, with a fractional inhibitory combination index (FICI) of 0.02. The sensitization effect of17c + FLC was further validated by the temporal fungicidal curve analysis. In addition,17c + FLC also demonstrated inhibitory effects on the mycelial transformation and biofilm formation of resistantC. albicans, and significantly reduced the expression of key genes related t...
Source: Medicinal Chemistry Research - July 24, 2023 Category: Chemistry Source Type: research

Using molecular networking and docking to explore arginase inhibitors among Drimys brasiliensis chemical constituents
This study has investigated whether the bark and leaves ofDrimys brasiliensis Miers (Winteraceae), a plant known for its antileishmanial effect, can inhibitLeishmania amazonensis arginase. IC50 values of 13.6 and 8.0  μg/mL were obtained for the ethanolic extracts fromD. brasiliensis bark and leaves, respectively. Liquid chromatography –high resolution mass spectrometry analysis of the bioactive extracts helped to identify ten compounds, including flavonoids, phenolic acids, and hydroxycinnamic acid derivatives. Among these compounds, flavonoids and chlorogenic acid are known for potentially inhibiting arginase, and t...
Source: Medicinal Chemistry Research - July 24, 2023 Category: Chemistry Source Type: research

Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans
In this study, a series of deguelin (Deg) derivative were prepared and identified with in vitro antifungal activity against drug-resistantC. albicans combined with fluconazole (FLC). The combination of Deg derivative17c and FLC exhibited the best activity, with a fractional inhibitory combination index (FICI) of 0.02. The sensitization effect of17c + FLC was further validated by the temporal fungicidal curve analysis. In addition,17c + FLC also demonstrated inhibitory effects on the mycelial transformation and biofilm formation of resistantC. albicans, and significantly reduced the expression of key genes related t...
Source: Medicinal Chemistry Research - July 24, 2023 Category: Chemistry Source Type: research

Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendiline and NPS R-467
AbstractSynthetic routes following a sequential MacMillan organocatalytic asymmetric α-fluorination protocol for aldehydes and then reductive amination, have allowed ready access to bioactive β-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro- γ-aminobutyric acid (3F-GABA) and was extended to β-fluoroamine stereoisomers of cinacalcet, tecalcet, fendiline and NPS R-467, all allosteric modulators of the calcium receptor (CaR). Stereoisomers of the fluorinated calcimimetic analogues were then assayed in a CaR receptor assay and a compariso n of β-fluoroamine matched pair stereoisomers rev...
Source: Medicinal Chemistry Research - July 24, 2023 Category: Chemistry Source Type: research