Molecular docking, characterization, ADME/toxicity prediction, and anti-ulcer activity of new quercetin derivatives on indomethacin-induced gastric ulcer in mice

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Salem M.B.; Saleh A.M.; Seif el-Din S.H.; Samir S.; Hammam O.A.; El-Lakkany N.M.

Journal: Toxicology and Applied Pharmacology

Publisher: Academic Press Inc.

Publication Date: March 2024

Volume / Issue: Volume 484

Article No.: 116880

ISSN: 0041008X

DOI: 10.1016/j.taap.2024.116880

Scopus: View on Scopus

PubMed: 38447874

Document Type: Article

Authors and Affiliations

Salem M.B., Pharmacology Department, Theodor Bilharz Research Institute, Giza, Egypt; Saleh A.M., Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of pharmacy (Boys), Al-Azhar University, Cairo, Egypt; Seif el-Din S.H., Pharmacology Department, Theodor Bilharz Research Institute, Giza, Egypt; Samir S., Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Giza, Egypt; Hammam O.A., Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt; El-Lakkany N.M., Pharmacology Department, Theodor Bilharz Research Institute, Giza, Egypt

Abstract

Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs. © 2024 Elsevier Inc.

Keywords

Famotidine; Gastric ulcer; Indomethacin; Molecular docking; Quercetin; TLR-4/MyD88/NF-κB signaling pathway; Animals; Gastric Mucosa; Humans; Mice; Molecular Docking Simulation; Myeloid Differentiation Factor 88; NF-kappa B; Stomach Ulcer; Toll-Like Receptor 4; Ulcer; ABC transporter subfamily B; antiulcer agent; beta actin; catalase; cyclooxygenase 1; cyclooxygenase 2; cytochrome P450 1A2; cytochrome P450 2C19; cytochrome P450 2C9; cytochrome P450 2D6; cytochrome P450 3A4; eosin; estrogen receptor; estrogen receptor alpha; glutathione; hematoxylin; immunoglobulin enhancer binding protein; indometacin; intimin; malonaldehyde; new drug; nitric oxide; protein MD 2; quercetin derivative; quercetin pentaacetyl; quercetin pentamethyl; thiopental; toll like receptor 4; translocated intimin receptor; unclassified drug; acute toxicity; anesthesia; animal experiment; animal model; animal tissue; antiinflammatory activity; antiulcer activity; Article; biochemical analysis; blood brain barrier; Caco-2 cell line; carcinogenicity; cell viability; cell viability assay; computer model; controlled study; cytotoxicity; drug absorption; drug bioavailability; drug determination; drug distribution; drug excretion; drug half life; drug metabolism; drug synthesis; drug toxicity; histology; human; human cell; immunohistochemistry; immunotoxicity; indomethacin-induced gastric ulcer; LD50; ligand binding; liver cell; liver toxicity; macrophage; male; mouse; mouse model; multidrug resistance; mutagenicity; nonhuman; oxidative stress; pathogenesis; pharmacological parameters; plasma protein binding; prediction; quantitative analysis; RAW 264.7 cell line; real time polymerase chain reaction; RNA extraction; signal transduction; stomach mucosa; therapeutic index; ulcer score; Vero cell line; Western blotting; animal; metabolism; pathology

Citation Information

Scopus Citations: 9

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