Drug design, development and therapy · 2026
Novel Hybrid Scaffold of Pyrazole, Thiazole, and [1,2,3]triazole: Eco-Friendly Synthesis by DABCO, Anti-HIV-1 RT, and In Silico Studies.
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Al-Saleem Muneera S M, Elhenawy Ahmed A, Al Sharif Ohoud F, Riyadh Sayed M, Zaki Magdi E A, Gomha Sobhi M
Аннотация
BACKGROUND: The emergence of drug-resistant HIV-1 strains and limitations of current reverse transcriptase (RT) inhibitors support the development of structurally novel antiviral scaffolds. Hybrid azole systems may provide complementary interactions within the HIV-1 RT binding pocket.Purpose: To synthesize novel pyrazole-thiazole-[1,2,3]triazole hybrids using an eco-friendly DABCO-mediated approach and evaluate their anti-HIV-1 RT activity and structure-activity relationships using experimental and computational methods.
METHODS: Fourteen hybrid compounds were synthesized from hydrazone-1-carbothioamide 3 through cyclo-condensation with hydrazonoyl chlorides 4a-j or 5a-d using DABCO, affording arylazo-thiazoles 6a-j and hydrazono-thiazol-4(5H)-ones 7a-d. Structures were characterized by IR, 1H-NMR, 13C-NMR, and mass spectrometry. Molecular docking against HIV-1 RT (PDB: 3V81) was used to prioritize candidates, and six compounds were evaluated using an ELISA-based RT inhibition assay with zidovudine as reference. DFT, molecular electrostatic potential, and intramolecular charge-transfer analyses were also performed.
RESULTS: The target compounds were obtained in 90-95% yields. The six tested derivatives showed IC50 values of 0.192-1.693 μg/mL. Compound 7a was the most active (IC50 = 0.192 ± 0.008 μg/mL), with activity comparable to zidovudine (0.201 ± 0.009 μg/mL; p = 0.74), and showed the most favorable docking energy (-6.37 kcal/mol) with a key Lys65 hydrogen bond. The hydrazono-thiazolone series 7 generally outperformed series 6. DFT analysis associated higher hardness and wider HOMO-LUMO gaps with improved activity.
CONCLUSION: Compound 7a represents a promising HIV-1 RT inhibitor lead, supported by consistent enzymatic, docking, and electronic-structure findings. Further cytotoxicity and cell-based antiviral studies are required to establish its selectivity and preclinical potential.
METHODS: Fourteen hybrid compounds were synthesized from hydrazone-1-carbothioamide 3 through cyclo-condensation with hydrazonoyl chlorides 4a-j or 5a-d using DABCO, affording arylazo-thiazoles 6a-j and hydrazono-thiazol-4(5H)-ones 7a-d. Structures were characterized by IR, 1H-NMR, 13C-NMR, and mass spectrometry. Molecular docking against HIV-1 RT (PDB: 3V81) was used to prioritize candidates, and six compounds were evaluated using an ELISA-based RT inhibition assay with zidovudine as reference. DFT, molecular electrostatic potential, and intramolecular charge-transfer analyses were also performed.
RESULTS: The target compounds were obtained in 90-95% yields. The six tested derivatives showed IC50 values of 0.192-1.693 μg/mL. Compound 7a was the most active (IC50 = 0.192 ± 0.008 μg/mL), with activity comparable to zidovudine (0.201 ± 0.009 μg/mL; p = 0.74), and showed the most favorable docking energy (-6.37 kcal/mol) with a key Lys65 hydrogen bond. The hydrazono-thiazolone series 7 generally outperformed series 6. DFT analysis associated higher hardness and wider HOMO-LUMO gaps with improved activity.
CONCLUSION: Compound 7a represents a promising HIV-1 RT inhibitor lead, supported by consistent enzymatic, docking, and electronic-structure findings. Further cytotoxicity and cell-based antiviral studies are required to establish its selectivity and preclinical potential.