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 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔGbind and Ki, 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.
Subject(s)
Antineoplastic Agents , COVID-19 Drug Treatment , Coordination Complexes , Ruthenium , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , 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-2ABSTRACT
Inhibitors of type 1 human immunodeficiency virus (HIV-1) reverse transcriptase are central to anti-HIV therapy. Most of their targets are enzymes, while very few could bind to viral RNA. Here we designed four new polypyridyl Ru(II) complexes, which could bind HIV-1 TAR RNA tightly and selectively by molecular recognition of hydrogen bonds, further stabilize the Ru(II)-RNA bound system by electrostatic attraction, and efficiently inhibit the Moloney murine leukemia virus (M-MuLV) and HIV-1 reverse transcriptase. The polypyridyl Ru(II) complexes also have physical and chemical advantages, including high chemical stability and photostability, sensitive spectroscopic responses to HIV TAR RNA, and low toxicity to normal cells. This work also provides valuable drug design strategies for acquired immune deficiency syndrome (AIDS) and other reverse transcriptase related disease research, such as hepatitis C virus (HCV), Ebola virus (EBOV), influenza A virus, and most recently the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Subject(s)
HIV-1 , Reverse Transcriptase Inhibitors , Ruthenium , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Humans , RNA , Reverse Transcriptase Inhibitors/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , SARS-CoV-2ABSTRACT
As SARS-CoV-2 is spreading rapidly around the globe, adopting proper actions for confronting and protecting against this virus is an essential and unmet task. Reactive oxygen species (ROS) promoting molecules such as peroxides are detrimental to many viruses, including coronaviruses. In this paper, metal decorated single-wall carbon nanotubes (SWCNTs) were evaluated for hydrogen peroxide (H2O2) adsorption for potential use for designing viral inactivation surfaces. We employed first-principles methods based on the density functional theory (DFT) to investigate the capture of an individual H2O2 molecule on pristine and metal (Pt, Pd, Ni, Cu, Rh, or Ru) decorated SWCNTs. Although the single H2O2 molecule is weakly physisorbed on pristine SWCNT, a significant improvement on its adsorption energy was found by utilizing metal functionalized SWCNT as the adsorbent. It was revealed that Rh-SWCNT and Ru-SWCNT systems demonstrate outstanding performance for H2O2 adsorption. Furthermore, we discovered through calculations that Pt- and Cu-decorated SWNCT-H2O2 systems show high potential for filters for virus removal and inactivation with a very long shelf-life (2.2 × 1012 and 1.9 × 108 years, respectively). The strong adsorption of metal decorated SWCNTs and the long shelf-life of these nanomaterials suggest they are exceptional candidates for designing personal protection equipment against viruses.