Abstract
Here, we describe machine learning models, predicted ADMET properties, and analysis in vitro activity of selected 4-iminohydantoin sulfamide derivatives with different N-substitution against human cytomegalovirus (HCMV). Among six compounds bearing aliphatic cyclic amine part with alkoxycarbonyl or CF3-diazirine substituents, four derivatives exhibited antiviral activity (EC50: 0.15–0.95 μM) against a wild-type laboratory HCMV (strain AD169) in human foreskin fibroblast cells comparable to that of ganciclovir (EC50: 0.39 μM), an anti-HCMV agent in clinical use. Two of the aliphatic cyclic amine-containing compounds showed higher potency (EC50: 0.13 and 0.54 μM) toward the resistant isolate (GDGRK17) compared to standard drug ganciclovir (EC50: 13.44 μM), and comparable to cidofovir (EC50: 0.11 µM). However, as with the wild-type strain, these hydantoins were more toxic and less selective than the standard drugs. In contrast to the primary assay, secondary analysis using quantitative polymerase chain reaction did not confirm the results of the primary one. The data obtained indicate that the 4-iminohydantoin sulfamide derivatives with alicyclic amine moiety may be useful for designing bioactive compounds against HCMV.
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Acknowledgements
These studies were funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN75N93019D00016 (SHJ). This work was supported by the National Research Foundation of Ukraine (Grant number 2020.01/0075) and by the NAS of Ukraine (within the additional departmental theme of research work in 2022 "Search and synthesis of antiviral agents among nitrogencontaining heterocycle derivatives").
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Zhirnov, V., Shablykin, O., Chumachenko, S. et al. In vitro activity of novel 4-iminohydantoin sulfamide derivatives against human cytomegalovirus. Chem. Pap. 78, 133–140 (2024). https://doi.org/10.1007/s11696-023-03038-1
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DOI: https://doi.org/10.1007/s11696-023-03038-1