The present study demonstrated the design and synthesis of novel 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives as putative inhibitors against various infective diseases. The title analogues were synthesized in a multi-step process, and their structures were verified through elemental analysis and a variety of spectral analyses (FT-IR, 1H NMR, 13C NMR, mass). Compounds 12a was identified as prospective lead compound against HIV-1 based on their high CDdocker interaction energy and stability among the developed derivatives, according to molecular docking and MD simulation experiments with HIV-1 RT. Compound 12a was found effective against HIV-1 in a cell-based experiment, preventing the virus from replicating in CEM-GFP cells infected with 0.5 MOI of HIV-1 NL4-1. In the RNA-dependent DNA polymerase (RDDP) activity of the HIV-1 RT enzyme using a cell free based RT assay, compound 12a showed a therapeutic index of 113 and an EC50 of 125.1 nM. All of the compounds inhibited SARS-CoV-2 replication in the VeroE6-GFP cell line to varying degrees; compound 10e, 12e, 12a, 12b, and 12c, in particular, showed considerable inhibitory activity. The compounds exhibited stronger antibacterial action against Gram-negative than Gram-positive bacteria in an antimicrobial assay, and a SAR analysis revealed that tri-substituted 1,3,5-triazine derivatives exhibited greater inhibitory activity than di-substituted ones. Additionally, 12d and 12e were found to be the most effective inhibitors of P. aeruginosa biofilms when tested against this bacterium. The most active inhibitors, 12a and 12e, were also tested for thermodynamic solubility at pH 7.4 via miniaturized shake-flask method. Here, their solubility was found to be significantly influenced by the presence of hydroxyl group and morpholine. In conclusion, our research demonstrated the significant inhibitory activity of 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives against HIV, SARS-CoV-2, and bacterial microorganisms.
Design, and synthesis of 2,4-thiazolidinedione substituted 1–3-5-triazine derivatives as anti-HIV agent via inhibition of reverse transcriptase along with anti-SARS CoV-2, antibacterial and antibiofilm activity
Corona, Angela;Tramontano, Enzo;
2025-01-01
Abstract
The present study demonstrated the design and synthesis of novel 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives as putative inhibitors against various infective diseases. The title analogues were synthesized in a multi-step process, and their structures were verified through elemental analysis and a variety of spectral analyses (FT-IR, 1H NMR, 13C NMR, mass). Compounds 12a was identified as prospective lead compound against HIV-1 based on their high CDdocker interaction energy and stability among the developed derivatives, according to molecular docking and MD simulation experiments with HIV-1 RT. Compound 12a was found effective against HIV-1 in a cell-based experiment, preventing the virus from replicating in CEM-GFP cells infected with 0.5 MOI of HIV-1 NL4-1. In the RNA-dependent DNA polymerase (RDDP) activity of the HIV-1 RT enzyme using a cell free based RT assay, compound 12a showed a therapeutic index of 113 and an EC50 of 125.1 nM. All of the compounds inhibited SARS-CoV-2 replication in the VeroE6-GFP cell line to varying degrees; compound 10e, 12e, 12a, 12b, and 12c, in particular, showed considerable inhibitory activity. The compounds exhibited stronger antibacterial action against Gram-negative than Gram-positive bacteria in an antimicrobial assay, and a SAR analysis revealed that tri-substituted 1,3,5-triazine derivatives exhibited greater inhibitory activity than di-substituted ones. Additionally, 12d and 12e were found to be the most effective inhibitors of P. aeruginosa biofilms when tested against this bacterium. The most active inhibitors, 12a and 12e, were also tested for thermodynamic solubility at pH 7.4 via miniaturized shake-flask method. Here, their solubility was found to be significantly influenced by the presence of hydroxyl group and morpholine. In conclusion, our research demonstrated the significant inhibitory activity of 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives against HIV, SARS-CoV-2, and bacterial microorganisms.
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