Medicinal Chemistry Research最新文献

Ribavirin (1) esters 4–36 have been synthesized and tested for their anti-inflammatory and anti-viral properties against SARS-CoV-2. The impaired host immune response known as cytokine release syndrome is one of the major causes of COVID-19 infection-related death. The current study aimed to assess compounds 4–36 against viral infection in Vero cells (viral titration, cytopathic effects, anti-viral efficacy, and results of treatment points) and anti-inflammatory activity against cytokines (IL-2, GM-CSF, IL-6, TNF-α, IFN-γ and IL-1β) were quantified at the protein level by using ELISA, oxidative burst assay, nitric oxide inhibition assay, anti-proliferative activity. Cytotoxicity of compounds was also determined. Compound 13 showed promising results against anti-inflammatory activity (100.80%, IC₅₀ = 0.40 ± 0.01 µM) and SARS-CoV-2 infection inhibition up to 80% (IC₅₀ = 1.42 ± 0.28). Nonetheless, further investigation is necessary to enhance and synthesize long-acting Ribavirin esters-based anti-inflammatory and SARS-CoV-2 medications based on the identified patterns.

Coordination complexes of cobalt represent a potential alternative to anticancer platinum-derived drugs owing to multiple activities and better toxicity profile. This work is aimed at generation of novel cobalt complexes based on peptide-conjugated diethylentriamine (Dien) ligand. Dien derivatives including SPPS-compliant Boc-protected N,N′-di(2-aminoethyl)glycine and its conjugate with RGD peptide derivative (compound 6) were synthesized. Cobalt(III) complexes of Dien and 6 were obtained and characterized. Both complexes exhibited comparable ATP-depleting activity in solution and in PC-3 and OVCAR-4 cancer cells. The complex of 6 showed profoundly increased prooxidant, cytotoxic, and apoptotic in vitro effects compared to the non-targeted counterpart. Both complexes bound DNA and caused its significant damage in the presence of glutathione or hydrogen peroxide. These results provide an important background for development of bioactive cobalt complexes conjugated with biospecific oligopeptides.

Protein kinase CK2 is a validated target for cancer therapy. Many natural products have shown inhibitory activity against CK2 as potential anti-cancer drug candidates. A compatible quantitative structure-activity relationship (QSAR) model of natural products is necessary to identify the structural determinants related to their biological activities and provides valuable clues for the discovery of natural leads as anticancer drugs. In this study, genetic algorithm (GA) and multiple linear regression (MLR) methods, combined with preferred molecular descriptors, were employed to build QSAR models of CK2 natural product inhibitors. The best model, composed of eight molecular descriptors, yielded Q²_Loo = 0.7914 and R² = 0.8220 for the training set and Q²_ext = 0.7921 and R²_ext = 0.7998 for the test set, indicating the model’s robust reliability and high predictability. As a proof of concept, a true external test set, distinct from the training and test sets, was synthesized and tested in vitro to verify the predictive ability of this model. The predicted pIC₅₀ values of 13 compounds showed less than 30% relative error (including 10 compounds with relative errors less than 20%), further validating the predictive performance of this model. And compound M18, M24, and M26 were identified as potential CK2 inhibitors with the predicted pIC₅₀ values of 11.29, 8.79, and 12.03 respectively. Furthermore, the underlying structural mechanisms through which key molecular descriptors influenced their inhibitory activities against CK2 were elucidated. All these results provide valuable information for the discovery of CK2 inhibitors.

Graphical Abstract

Chromanones are a subset of the benzopyran family, and display diverse biological activities, both as natural products and synthetic derivatives. Among these, we selected the natural product uniflorol, a 4-chromanone with an α,β-unsaturated ketone side chain, as a lead compound due to its reported anti-leishmanial properties. We designed and synthesised four series of novel compounds, varying the substitution patterns around the benzopyran core, and evaluated the compounds for anti-leishmanial activity against amastigotes of L. infantum. We prepared and characterised 24 novel compounds; upon screening, 12 compounds demonstrated activity values of <50 μM, with the most potent compound, 16d, having an IC₅₀ of 7.29 μM. Activity was favoured in compounds bearing a phenylalkenyl motif, such as cinnamyl, styryl or a more lipophilic extension, and amide analogues retained activity. Uniflorol analogues display promise as novel architectures towards the development of potential anti-leishmanial agents.

Substituted furan carboxamide and Schiff base derivatives were evaluated for their hypolipidemic activity. Fourteen derivatives were synthesised: substituted-furan-2-carboxamides of acetophenones, anilines, and benzophenones a (1–8), furan-3-carboxamide (c1), and imines derivatives b (1–5). These compounds were synthesised, purified and fully characterised. All the new derivatives were verified in-vivo utilising Triton WR-1339 induced hyperlipidemic rats as animal model. The potential agents were administered via intraperitoneal injection of 20 mg/kg. Fenofibrate (with a dose 100 mg/kg, orally) was used in this research to validate the model. Remarkably, the new derivatives a (1–8), b (1–5) and c1 have shown significant effect against the whole lipid profile; by lowering the plasma triglyceride (TG), plasma total cholesterol (TC), low-density lipoprotein (LDL) level and elevating high-density lipoproteins (HDL) plasma levels comparing to the hyperlipidemic rats. The agents reduce TG with most significant results by (97%, 96%, 87% and 86%) relating to a1, a3, a8 and b5 respectively. Favourably, some of the proposed agents are more significant in reducing TG than fenofibrate. Some agents reduce LDL with most significant results by (76%, 72%, 60%, 60% and 60%) relating to a1, a3, a5, a8 and b5 respectively, and to a lower extent they increase HDL levels with most significant results by (75%, 64%, and 48%) for a1, a3, and a5 respectively. All the new derivatives were computationally docked at the hPPAR-α active site as possible target for these derivatives. The binding affinities were reported and showed good correlation to the in-vivo results as antihyperlipidemic agents.

Because of CO’s known endogenous signaling roles and its demonstrated pharmacological activity at low and safe concentrations, there is considerable interest in chemical strategies that allows for generation of carbon monoxide from organic molecules under near-physiological conditions. Along this line, we report our work on studying the ability of iron porphyrin to catalyze CO generation from phenylpyruvic acid (PPA). To utilize this system for potential CO therapeutics and diagnostic applications, an activated charcoal formulation was designed, optimized, and assessed. Among the various iron porphyrin analogs studied, tetrakis(pentafluorophenyl)porphyrin iron (III) (TPFP) immobilized on activated charcoal was found to produce up to 60% CO from PPA. This chemistry could also be utilized in PKU diagnostics for quantification of PPA accumulation in urine. This catalytic conversion allows for the use of CO generation to rapidly quantify PPA concentration in urine samples. Another potential relevance of this CO generation pathway is the extent to which it could undergo in vivo as an endogenous source of CO.

With the increasing of Candida albicans infections year by year, and the widespread use of azole drugs, especially fluconazole has led to the emergence of drug resistance. Therefore, new antifungal agents are urgent needed. In this work, we synthesized a series of tryptanthrin derivatives, and all compounds were evaluated for antifungal activities against Candida albicans in vitro. The results indicated that most compounds combined with fluconazole showed good antifungal activity against drug-resistant Candida albicans. Especially, compound 5b combined with fluconazole had an excellent synergistic effect, with MIC₅₀ value of 0.94 μg/mL, and the FICI value of 0.005. Further mechanism study demonstrated that compound 5b significantly inhibited the hyphal growth and biofilm formation of Candida albicans. Compound 5b combined with fluconazole could be considered as a novel antifungal agent.