2. Academic Validation
  3. Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity

Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity

  • Eur J Med Chem. 2023 Jan 5;245(Pt 2):114902. doi: 10.1016/j.ejmech.2022.114902.
Rossella Fioravanti 1,  Eleonora Proia 2,  Ivan N Tyurenkov 3,  Denis V Kurkin 4,  Dmitry A Bakulin 5,  Nikolay S Kovalev 6,  Dmitry S Sheikin 7,  Ivan A Kirillov 8,  Maxim B Nawrozkij 9,  Andrey A Vernigora 10,  Leila L Brunilina 11,  Francesco Fiorentino 12,  Milan Mladenović 13,  Dante Rotili 14,  Rino Ragno 15
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy. Electronic address: rossella.fioravanti@uniroma1.it.
  • 2 Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy. Electronic address: eleonora.proia@uniroma1.it.
  • 3 Volgograd State Medical University, Novorossiyskaya St. 39, 400087, Volgograd, Russia. Electronic address: fibfuv@mail.ru.
  • 4 Volgograd State Medical University, Novorossiyskaya St. 39, 400087, Volgograd, Russia. Electronic address: mbfdoc@gmail.com.
  • 5 Volgograd State Medical University, Novorossiyskaya St. 39, 400087, Volgograd, Russia. Electronic address: strannik986@mail.ru.
  • 6 Volgograd State Medical University, Novorossiyskaya St. 39, 400087, Volgograd, Russia. Electronic address: kovalev.volgmed@gmail.com.
  • 7 Volgograd State Technical University, 28 Lenina Ave., 400005, Volgograd, Russia. Electronic address: d.sheikin@yandex.ru.
  • 8 Volgograd State Technical University, 28 Lenina Ave., 400005, Volgograd, Russia. Electronic address: kirillow.vania@yandex.ru.
  • 9 Division of Translational Medicine, Sirius University of Science and Technology, Sochi, Olympic avenue, 1, Russia. Electronic address: maxim.nawrozkij@gmail.com.
  • 10 Volgograd State Technical University, 28 Lenina Ave., 400005, Volgograd, Russia. Electronic address: v.a.a_@mail.ru.
  • 11 Volgograd State Technical University, 28 Lenina Ave., 400005, Volgograd, Russia. Electronic address: leila_1974@mail.ru.
  • 12 Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy. Electronic address: f.fiorentino@uniroma1.it.
  • 13 Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia. Electronic address: mmladenovic@kg.ac.rs.
  • 14 Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy. Electronic address: dante.rotili@uniroma1.it.
  • 15 Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy; Rome Center for Molecular Design, Department of Drug Chemistry and Technologies, Sapienza Università di Roma, P. le A. Moro 5, 00185, Roma, Italy. Electronic address: rino.ragno@uniroma1.it.
PMID: 36403514 DOI: 10.1016/j.ejmech.2022.114902
Abstract

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the Animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype.

Keywords

3D-QSAR; Antidepressant; Anxiolytic; DABO; GABA-A; Melatonin MT-1 and MT-2 receptors; Molecular docking; Nootropic; Performance enhancing agents; Pyrimidine thioethers; Sigma-1.

Figures
Products