Synthesis, molecular docking, ADMET study and in vitro pharmacological research of 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione as a promising non-opioid analgesic drug

Авторы

DOI:

https://doi.org/10.3897/rrpharmacology.8.80504

Аннотация

Introduction: The discovery of novel drugs that can block the transmission of pain signals for treating the pain of various etiologies is an urgent topic in pharmaceutics. The aim of this paper is to synthesize and to investigate in vitro and in silico characteristics of a promising novel compound: 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione (HSV-DKH-0450).

Materials and methods: The specific activity and the inhibitory mechanism of HSV-DKH-0450 were studied using the HEK293 culture cells expressing the IPTG-induced TRPA1 ion channels. Cardiotoxicity was determined by estimating the binding of HSV-DKH-0450 to the hERG channel. Inhibition of human liver cytochromes was determined by the effect on the activity of cytochromes 1A2, 2C9, 2D6, 2C8, and 3A4. Cellular toxicity was assessed by the effect on the viability of human hepatocytes. ADMET properties were evaluated using admetSAR and SwissADME web-based tools. Molecular docking was carried out using AutoDock Vina tools to predict the binding affinity of all HSV-DKH-0450 stereoisomers toward the TRPA1 and TRPV1 receptors.

Results and discussion: In silico predictions of ADMET properties of HSV-DKH-0450 showed that it has optimal pharmaceutical profiles. A series of in vitro pharmacological studies revealed that HSV-DKH-0450 is a promising antagonist of the TRPA1 ion channel with the IC50 of 91.3 nM. The molecular docking of HSV-DKH-0450 stereoisomers against the TRPA1 and TRPV1 receptors demonstrates that they all are characterized by an approximately similar high binding affinity.

Conclusion: The obtained data for substance HSV-DKH-0450 look promising for its further development as a potential therapeutic agent for pain relief.

Ключевые слова:

antagonist, drug discovery, ion channels, molecular docking, TRPA1, TRPV1

Библиографические ссылки

Araki M, Kanda N, Iwata H, Sagae Y, Masuda K, Okuno Y (2020) Identification of a new class of non-electrophilic TRPA1 agonists by a structure-based virtual screening approach. Bioorganic Medicinal Chemistry Letters 30(11): е127142. https://doi.org/10.1016/j. bmcl.2020.127142 [PubMed]

Вклад авторов

Aleksey D. Kravchenko, I.M. Sechenov First Moscow State Medical University (Sechenov University)

Postgraduate student of the Department of Industrial Pharmacy.

The author participated in synthesis of the compounds, was engaged in writing and editing the article.

Natalia V. Pyatigorskaya, I.M. Sechenov First Moscow State Medical University (Sechenov University)

Doctor Habil. of Sciences of Pharmacy, Head of the Department of Industrial Pharmacy.

The author suggested the idea of the article, made contributions to the design of the article and participated in drafting the article.

Galina E. Brkich, I.M. Sechenov First Moscow State Medical University (Sechenov University)

Head of the Center for Pharmaceutical Technologies of the Institute of Translational Medicine
and Biotechnology.

The author made contributions to the design of the article and participated in drafting the article.

Larysa V. Yevsieieva, V.N. Karazin Kharkiv National University

Assistant of the Department of Organic Chemistry.

The author was engaged in writing and editing the article and prepared the final version of the article.

Alexander V. Kyrychenko, V.N. Karazin Kharkiv National University

Doctor Habil. of Chemical Sciences, Professor at Department of Organic Chemistry.

The author was engaged in molecular docking calculations, in manuscript writing and editing the final version of the article.

Sergiy M. Kovalenko, V.N. Karazin Kharkiv National University; I.M. Sechenov First Moscow State Medical University (Sechenov University)

Doctor Habil. of Chemical Sciences, Professor of the Department of Organic Chemistry;
Professor of Department of Pharmaceutical Technology and Pharmacology of the Institute of Pharmacy.

The author was engaged in molecular design and synthesis of the compounds. The author analyzed and interpreted the data, was engaged in writing and editing the article.

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Опубликован

30.03.2022

Как цитировать

Kravchenko AD, Pyatigorskaya NV, Brkich GE, Yevsieieva LV, Kyrychenko AV, Kovalenko SM (2022) Synthesis, molecular docking, ADMET study and in vitro pharmacological research of 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione as a promising non-opioid analgesic drug. Research Results in Pharmacology 8(1): 1–11. https://doi.org/10.3897/rrpharmacology.8.80504

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