Recent Advances in Design and Development of Diazole and Diazine Based Fungicides (2014-2023).

With fungal diseases posing a major threat to agricultural production, the application of fungicides to control related diseases is often considered necessary to ensure the world's food supply. The search for new bioactive agents has long been a priority in crop protection due to the continuous development of resistance against currently used types of active compounds. Heterocyclic compounds are an inseparable part of the core structures of numerous lead compounds, these rings constitute pharmacophores of a significant number of fungicides developed over the past decade by agrochemists. Among heterocycles, nitrogen-based compounds play an essential role. To date, diazole (imidazole and pyrazole) and diazine (pyrimidine, pyridazine, and pyrazine) derivatives make up an important series of synthetic fungicides. In recent years, many reports have been published on the design, synthesis, and study of the fungicidal activity of these scaffolds, but there was a lack of a comprehensive classified review on nitrogen-containing scaffolds. Regarding this issue, here we have reviewed the published articles on the fungicidal activity of the diazole and diazine families. In current review, we have classified the molecules synthesized so far based on the size of the ring.

Biological Activity of Novel Pyrrole Derivatives as Antioxidant Agents Against 6-OHDA Induced Neurotoxicity in PC12 Cells.

Background: Neuroinflammation and oxidative stress are critical factors involved in the pathogenesis of Parkinson's disease (PD), the second most common progressive neurodegenerative disease. Additionally, lipid peroxidation end products contribute to inflammatory responses by activating pro-inflammatory genes. Lipid peroxidation occurs as a result of either the overproduction of intracellular reactive oxygen species (ROS) or the reaction of cyclooxygenases (COXs). Objectives: In this study, we examined the role of 1,5-diaryl pyrrole derivatives against the neurotoxic effects of 6-hydroxydopamine (6-OHDA) in a cellular model of PD. Methods: PC12 cells were pre-treated with compounds 2-(4-chlorophenyl)-5-methyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole (A), 2-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole (B), and 1-(2-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-1H-pyrrole (C), respectively, 24 h before exposure to 6-OHDA. We conducted various assays, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT), ROS, and lipid peroxidation assays, Hoechst staining, Annexin V/PI, Western blotting analysis and ELISA method, to assess the neuroprotective effects of pyrrole derivatives on 6-OHDA-induced neurotoxicity. Results: Our results demonstrated that apoptosis induction was inhibited by controlling the lipid peroxidation process in the in vitro model following pre-treatment with compounds A, B, and, somehow, C. Furthermore, compounds A and C likely act by suppressing the COX-2/PGE2 pathway, a mechanism not attributed to compound B. Conclusions: These findings suggest that the novel synthetic pyrrolic derivatives may be considered promising neuroprotective agents that can potentially prevent the progression of PD.

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.

Pyrazole Derivatives Induce Apoptosis via ROS Generation in the Triple Negative Breast Cancer Cells, MDA-MB-468.

BACKGROUND: Triple-negative breast cancer accounts for approximately 15-20% of all breast carcinomas and is associated with earlier age of onset, aggressive clinical course, and dismal prognosis. A series of 1,3-diaryl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1 H-Pyrazole and 1,3-diaryl-5- (3,4,5-trimethoxyphenyl)- 1 H-Pyrazole were evaluated for their anticancer activity against MDA-MB-468, human triple negative breast cancer cell line. METHODS: The cytotoxic effects of Pyrazole derivatives on the growth of MDA-MB-468 and AGO1522 were determined using MTT assay. Annexin-V-FITC and PI staining were performed to detect apoptosis and cell cycle distribution using Flow cytometry. The level of Reactive oxygen species (ROS) formation and caspase 3 activity were determined accordingly. RESULTS: Pyrazole derivatives induced a dose and time-dependent cell toxicity in MDA-MB-468 compared with untreated cells. The results showed that 3-(4-methoxyphenyl)-1-(p-tolyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-Pyrazole (3f) was the most active compound with IC50 values 14.97 µM and 6.45 µM compared with Paclitaxel with IC50 values 49.90 µM and 25.19 µM, after 24 and 48 hours, respectively. Upon treatment with 14.97 µM of 3f after 24 h, the compound induced cell cycle arrest in S phase. 3f provoked apoptosis was accompanied by the elevated level of ROS and increased caspase 3 activity in MDA-MB-468 cells compared with untreated cells. CONCLUSION: The overall results of the present study provided evidence for the cytotoxicity of compound 3f against MDA-MB-468 cells in comparison to reference standard, Paclitaxel. It proves that compound 3f can trigger apoptosis through ROS production and caspase 3 activation. These bring supportive data for future investigations that will lead to their use in cancer therapy. 
.

Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel.

Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of -7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.

Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives.

BACKGROUND: During recent years, a number of anti-tubulin agents were introduced for treatment of diverse types of cancer. Despite their potential in the treatment of cancer, drug resistance and adverse toxicity, such as peripheral neuropathy, are some of the negative effects of anti-tubulin agents. Among anti-tubulin agents, indibulin was found to cause minimal peripheral neuropathy. Thus far, however, indibulin has not entered clinical usage, caused in part by its poor aqueous solubility and other developmental problems in preclinical evaluation. OBJECTIVES: With respect to need for finding potent and safe anticancer agents, in our current research work, we synthesized several indibulin-related diarylpyrrole derivatives and investigated their anti-cancer activity. METHODS: Cell cultur studies were perfomred using the MTT cell viability assay on the breast cancer cell lines MCF-7, T47-D, and MDA-MB231 and also NIH-3 T3 cells as representative of a normal cell line. The activity of some of the synthesized compounds for tubulin interaction was studied using colchicine binding and tubulin polymerization assays. The annexin V-FITC/PI method and flow cytometric analysis were used for studying apoptosis induction and cell cycle distribution. RESULTS AND CONCLUSION: Two of the synthesized compounds, 4f and 4 g, showed high activity on the MDA-MB231 cell line (IC50 = 11.82 and 13.33 µM, (respectively) and low toxicity on the normal fibroblast cells (IC50 > 100 µM). All of the tested compounds were more potent on T47-D cancer cells and less toxic on NIH-3 T3 normal cells in comparison to reference compound, indibulin. The tubulin polymerization inhibition assay and [3H]colchicine binding assay showed that the main mechanism of cell death by the potent synthesized compounds was not related to an interaction with tubulin. In the annexin V/PI staining assay, the induction of apoptosis in the MCF-7 and MDA-MB231 cell lines was observed. Cell cycle analysis illustrated an increased percentage of sub-G-1 cells in the MDA-MB231 cell line as a further indication of cell death through induction of apoptosis. Graphical abstract Novel Indibulin analogous as anti-breast cancer agents.

Synthesis and biological evaluation of 5-benzylidenerhodanine-3-acetic acid derivatives as AChE and 15-LOX inhibitors.

A series of 5-benzylidenerhodanine-3-acetamides bearing morpholino-, 4-arylpiperazinyl-, or 4-benzylpiperidinyl- moieties were synthesized and their inhibitory activities against acetylcholinesterase (AChE) were evaluated. Alteration of amide part and substitution on the benzylidene moiety resulted in change of anti-AChE activity. The most active compound was the 1-benzylpiperidinyl derivative containing 4-(dimethylamino)benzylidene scaffold. Notably, the intermediate compounds, namely 5-arylidene-rhodanine-3-acetic acids (3), showed mild inhibitory activity against 15-lipoxygenase (15-LOX), while the final compound 4 showed no activity against 15-LOX.