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Synthesis, Molecular Docking and ?-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives.

ABSTRACT: ?-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of ?-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (1?22) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against ?-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and ?-glucuronidase, 1, 4, and 6 compounds were docked into the active binding site of ?-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and ?-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-?-glucuronidase complexes.

SUBMITTER: Anouar EH

PROVIDER: S-EPMC6429331 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Synthesis, Molecular Docking and β-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives.

Anouar El Hassane EH Moustapha Moustapha Eid ME Taha Muhammad M Geesi Mohammed H MH Farag Zeinab R ZR Rahim Fazal F Almandil Noor Barak NB Farooq Rai Khalid RK Nawaz Muhammad M Mosaddik Ashik A

Molecules (Basel, Switzerland) 20190308 5

β-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of β-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and d ...[more]

PMID: 30857263

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Project description:Purpose:A new series of tetrazole derivatives, which are renowned antimicrobials possessing a five-membered aromatic heterocyclic group, are synthesized herein and subjected to antimicrobial and cytotoxicity screening. Methods:The tetrazole derivatives were synthesized via ultrasonication using Mannich base condensation. Structural verification of the products was performed using IR, 1H NMR, and 13C NMR spectroscopy, as well as mass spectroscopic and elemental analyses. The compounds were then screened for antimicrobial and cytotoxic activity against HepG2 (liver), MCF-7 (breast), and HeLa (cervical) cell lines. Inter- and intra-molecular binding interactions were determined using molecular docking studies. The exact binding mode between the most active tetrazole derivatives (ie, 1b, 2a, and 2b) and the proteins (ie, 4OR7, 1AI9, and 4FM9) was established using Autodock Vina 1.1.2 software and compared to the binding mode of the reference compounds (ie, cefazolin, clotrimazole, and fluorouracil). Results:Compound 1b was extremely active against Enterococcus faecalis relative to the positive control cefazolin. Compounds 1b and 1e were active against Candida albicans and Microsporum audouinii compared to the positive control clotrimazole in antifungal screening. The HepG2 (liver) and MCF-7 (breast) cancer cell lines were particularly susceptible to the synthesized compounds. Compared to the control compound fluorouracil, 2a and 2b were extremely active against all three cancer cell lines. Molecular docking studies showed that 2b exhibited higher binding affinity (-7.8 kcal/mol) to the 4OR7 protein than the control cefazolin (-7.2 kcal/mol). Conclusion:Generally, 1b, 2a, and 2b exhibited impressive inhibitory capabilities in antibacterial, antifungal, and cytotoxic screenings relative to the reference compounds. The results of the molecular docking studies and both the microbial and anticancer screenings indicate that these novel derivatives could be developed into potential therapeutic agents for medical applications.

Dataset Information

Synthesis, Molecular Docking and ?-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives.

Publications

Synthesis, Molecular Docking and β-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives.

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