A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities

Nenad Janković; Emilija Milović; Jelena Đorović Jovanović; Zoran Marković; Milan Vraneš; Tatjana Stanojković; Ivana Matić; Marija Đorđić Crnogorac; Olivera Klisurić; Miroslav Cvetinov; Syed Nasir Abbas Bukhari

doi:10.1016/j.cbi.2022.110025

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities

Chem Biol Interact. 2022 Aug 25:363:110025. doi: 10.1016/j.cbi.2022.110025. Epub 2022 Jun 22.

Affiliations

¹ University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Science, Jovana Cvijića bb, Kragujevac, 34000, Serbia. Electronic address: nenad.jankovic@kg.ac.rs.
² University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Science, Jovana Cvijića bb, Kragujevac, 34000, Serbia.
³ Faculty of Science, Department of Chemistry, Biochemistry and Environmental Protection, University of Novi Sad, Trg Dositeja Obradovića 3, 21000, Novi Sad, Serbia.
⁴ Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia.
⁵ University of Novi Sad, Faculty of Science, Department of Physics, Trg Dositeja Obradovića 3, 21000, Novi Sad, Serbia.
⁶ Academy of Arts, University of Novi Sad, Đure Jakšića 7, Novi Sad, Serbia.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 72388, Saudi Arabia.

Abstract

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 M^pro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔG_bind and K_i, which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept "one drug curing two diseases" could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time.

Keywords: Anticancer; COVID-19; Ruthenium; SARS-CoV-2 M(pro); Tetrahydropyrimidines.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
COVID-19 Drug Treatment*
Cell Line, Tumor
Coordination Complexes* / chemistry
Coordination Complexes* / pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Ruthenium* / chemistry
Ruthenium* / pharmacology
SARS-CoV-2

Substances

Antineoplastic Agents
Coordination Complexes
Ruthenium