Synthesis and molecular docking studies of new aryl imeglimin derivatives as a potent antidiabetic agent in a diabetic zebrafish model.

Diabetes mellitus (DM) is a persistent, progressive, and multifaceted disease characterized by elevated blood glucose levels. Type 2 diabetes mellitus is associated with a relative deficit in insulin mainly due to beta cell dysfunction and peripheral insulin resistance. Metformin has been widely prescribed as a primary treatment option to address this condition. On the other hand, an emerging glucose-reducing agent known as imeglimin has garnered attention due to its similarity to metformin in terms of chemical structure. In this study, an innovative series of imeglimin derivatives, labeled 3(a-j), were synthesized through a one-step reaction involving an aldehyde and metformin. The chemical structures of these derivatives were thoroughly characterized using ESI-MS, 1H, and 13C NMR spectroscopy. In vivo tests on a zebrafish diabetic model were used to evaluate the efficacy of the synthesized compounds. All compounds 3(a-j) showed significant antidiabetic effects. It is worth mentioning that compounds 3b (FBS = 72.3 ± 7.2 mg/dL) and 3g (FBS = 72.7 ± 4.3 mg/dL) have antidiabetic effects comparable to those of the standard drugs metformin (FBS = 74.0 ± 5.1 mg/dL) and imeglimin (82.3 ± 5.2 mg/dL). In addition, a docking study was performed to predict the possible interactions between the synthesized compounds and both SIRT1 and GSK-3ß targets. The docking results were in good agreement with the experimental assay results.

Drug repurposing against Candida auris: A systematic review.

Candida auris is a drug-resistant pathogen with several reported outbreaks. The treatment of C. auris infections is difficult due to a limited number of available antifungal drugs. Thus, finding alternative drugs through repurposing approaches would be clinically beneficial. A systematic search in PubMed, Scopus and Web of Science databases, as well as Google Scholar up to 1 November 2021, was conducted to find all articles with data regarding the antifungal activity of non-antifungal drugs against the planktonic and biofilm forms of C. auris. During database and hand searching, 290 articles were found, of which 13 were eligible for inclusion in the present study. Planktonic and biofilm forms have been studied in 11 and 8 articles (with both forms examined in 6 articles), respectively. In total, 22 and 12 drugs/compounds have been reported as repositionable against planktonic and biofilm forms of C. auris, respectively. Antiparasitic drugs, with the dominance of miltefosine, were the most common repurposed drugs against both forms of C. auris, followed by anticancer drugs (e.g. alexidine dihydrochloride) against the planktonic form and anti-inflammatory drugs (e.g. ebselen) against the biofilm form of the fungus. A collection of other drugs from various classes have also shown promising activity against C. auris. Following drug repurposing approaches, a number of drugs/compounds from various classes have been found to inhibit the planktonic and biofilm forms of C. auris. Accordingly, drug repurposing is an encouraging approach for discovering potential alternatives to conventional antifungal agents to combat drug resistance in fungi, especially C. auris.

Isoindolin-1-ones Fused to Barbiturates: From Design and Molecular Docking to Synthesis and Urease Inhibitory Evaluation.

Helicobacter pylori-induced ulcers and gastric cancer have been one of the main obstacles that the human community has ever struggled with, especially in recent decades. Several different attempts have been made to eradicate this group. One of the most widely used attempts is to inhibit the critical enzyme that facilitates its survival, the urease enzyme. Therefore, in this study, isoindolin-1-ones fused to barbiturates were designed, synthesized, and evaluated for their in vitro urease inhibitory activity as novel inhibitors for the urease enzyme. The synthesis route consisted of two steps. These steps increased the yield rate and decreased the percentage of byproducts while approaching green chemistry using ethanol and water as green solvents and microwave irradiation instead of conventional methods. In vitro urease inhibitory results indicated that all the compounds had higher inhibitory activity than the standard inhibitor, thiourea, and compound 5b proved to be the most potent inhibitor (IC50 = 0.82 ± 0.03 µM). A molecular docking study was performed to understand the interaction between compounds 5a-n and Jack bean urease enzyme. The results of the molecular docking study were also in harmony with the in vitro results, which are discussed in detail later in this study.

Novel benzimidazole derivatives; synthesis, bioactivity and molecular docking study as potent urease inhibitors.

BACKGROUND: Benzimidazole derivatives are widely used to design and synthesize novel bioactive compounds. There are several approved benzimidazole-based drugs on the market. OBJECTIVES: In this study, we aimed to design and synthesize a series of novel benzimidazole derivatives 8a-n that are urease inhibitors. METHODS: All 8a-n were synthesized in a multistep. To determine the urease inhibitory effect of 8a-n, the urease inhibition kit was used. The cytotoxicity assay of 8a-n was determined using MTT method. Molecular modelling was determined using autodock software. RESULTS: All 8a-n were synthesized in high yield, and their structures were determined using 1H-NMR, 13C-NMR, MS, and elemental analyses. In compared to thiourea and hydroxyurea as standards (IC50: 22 and 100 µM, respectively), all 8a-n had stronger urease inhibition activity (IC50: 3.36-10.81 µM). With an IC50 value of 3.36 µM, 8e had the best enzyme inhibitory activity. On two evaluated cell lines, the MTT cytotoxicity experiment revealed that all 8a-n have IC50 values greater than 50 µM. Finally, a docking investigation revealed a plausible way of interaction between the 8e and 8d and the enzyme's active site's key residues. CONCLUSION: The synthesized benzimidazole derivatives exhibit high activity, suggesting that further research on this family of compounds would be beneficial to finding a potent urease inhibitor.

New weapons to fight a new enemy: A systematic review of drug combinations against the drug-resistant fungus Candida auris.

Candida auris is an emerging and drug-resistant pathogen. Drug combination is a promising approach against such pathogens. This study was conducted to provide an overview of all the studied drug combinations against C. auris. Relevant articles reporting results of any drug/non-drug combinations against C. auris were found by a systematic search in PubMed, Scopus and Web of Science (ISI), and in Google Scholar up to 1 October 2020. From 187 articles retrieved in the primary search, 23 met the inclusion criteria. In total, 124 different combinations including antifungal with antifungal (45), antifungal with other antimicrobials (11), antifungal with non-antimicrobials (32), antifungal with natural compounds (25) and between natural compounds (11) have been reported. Complete or partial synergistic effects have been reported for 3 out of 45 (6.67%) combinations of two antifungal agents, 8 out of 11 (72.73%) combinations involving antifungal agents and antimicrobials, 15 out of 32 (46.88%) of combinations between antifungal agents with non-antimicrobials, 16 out of 25 (64%) of combinations involving antifungal agents and natural compounds, and 3 out of 11 (22.27%) of combinations involving multiple natural compounds. Antagonistic interactions have been reported for 1 out of 32 (3.13%) and 8 out of 25 (32%) of combinations between antifungal drugs with non-antimicrobials and with natural compounds, respectively. Different drugs/compounds could potentiate the activity of antifungal drugs using this approach. However, despite the availability of this promising initial data, many more studies will be required to elucidate whether favourable interactions observed in vitro might translate into tangible clinical benefits.