Design, Synthesis, and Investigation of Cytotoxic Effects of 5-Hydroxyindole-3-Carboxylic Acid and Ester Derivatives as Potential Anti-breast Cancer Agents.

Breast cancer is a deadly disease with a high prevalence rate among females. Despite several treatments, scientists are still engaged in finding less invasive treatments for this disease. The cellular proliferation rate and cell viability survey are critical to assess the drug's effect on both normal and malignant cell populations. Indole derivatives are promising candidates for their cytotoxic effect causing on breast cancer cells; however, they are less toxic on normal cells. This study synthesized 23 novel 5-hydroxyindole-3-carboxylic acids and related esters featuring various linear, cyclic, and primary aromatic amines. The MTT assay indicated the cytotoxicity of all acid and ester derivatives against the MCF-7 cells with no significant cytotoxicity on normal human dermal fibroblasts cells. Compound 5d, an ester derivative possessing a 4-methoxy group, was the most potent compound, with a half-maximal effective concentration of 4.7 µM. Compounds 5a, 5d, and 5l bearing ester group in their structure demonstrated cytotoxicity values < 10 µM against the MCF-7 cell line and were safe for advanced screening.

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core.

INTRODUCTION: The attractive biological actions of the eicosatrienoic acids (EETs) and endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain. METHODS: In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan- induced paw edema 5h after carrageenan injection compared to the control group compound. In addition, compound 7d exhibited a significant reduction in pain scores compared to the control group. RESULTS: Docking studies showed that the presented dual inhibitors could bind to the essential residues in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties suggests that these dual inhibitors could potentially be orally active agents. CONCLUSION: These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.

Synthesis of green benzamide-decorated UiO-66-NH2 for biomedical applications.

Metal-organic frameworks (MOFs) biocompatible systems can host enzymes/bacteria/viruses. Herein we synthesized a series of fatty acid amide hydrolase (FAAH)-decorated UiO-66-NH2 based on Citrus tangerine leaf extract for drug delivery and biosensor applications. Five chemically manipulated FAAH-like benzamides were localized on the UiO-66-NH2 surface with physical interactions. Comprehensive cellular and molecular analyses were conducted on HEK-293, HeLa, HepG2, PC12, MCF-7, and HT-29 cell lines (cytotoxicity assessment after 24 and 48 h). MTT results proved above 95 and 50% relative cell viability in the absence and presence of the drug, respectively. A complete targeted drug-releasing capability of nanocarriers was demonstrated after capping with leaf extract from Citrus tangerine, with a stimuli-responsive effect in acidic media. Targeted delivery was complete to the nucleus and cytoplasm of HT-29 cell, but merely to the cytoplasm of HeLa cell lines. Nanocarrier could be targeted for drug delivery to the cytoplasm of the HeLa cell line and to both the nucleus and cytoplasm of HT-29 cell lines. MOF-based nanocarriers proved authentic in vivo towards kidney and liver tissues with targeted cancerous cells efficiently. Besides, FAAH-like molecules revealed optical biosensor potential with high selectivity (even ˂5 nM LOD) towards ssDNA, sgRNA, and Anti-cas9 proteins.

Para-Aminobenzohydrazide Derivatives as Fatty Acid Amide Hydrolase Inhibitors: Design, Synthesis and Biological Evaluation.

The endocannabinoid system plays an important neuromodulatory role in the periphery and central nervous system, which can regulate several physiological processes. The inhibition of enzymatic activities responsible for hydrolysis anandamide and other endogenous fatty acid amides, enhances cannabinoid receptors activity indirectly that may prove to be useful drugs for the treatment of range of ailments including pain, anxiety, and other central nervous system disorders. In this study, we designed, synthesized, and evaluated novel fatty acid amide hydrolase (FAAH) inhibitors based on 4-aminobenzohydrazide derivatives. Most of the synthesized compounds exhibited a proper affinity for the catalytic triad of FAAH in docking studies and had a considerable in-vitro FAAH inhibitory activity in comparison with JZL-195, a potent inhibitor of FAAH. Compound 2-(2-(4-(2-carboxybenzamido) benzoyl) hydrazine-1-carbonyl) benzoic acid, 12, was found to be the most potent inhibitor with IC50 value of 1.62 nM targeting FAAH enzyme.