ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

In vitro activity of novel 4-iminohydantoin sulfamide derivatives against human cytomegalovirus

Victor Zhirnov, Oleh Shablykin, Svitlana Chumachenko, Yurii Kornii, Kathy A. Keith, Emma A. Harden, Caroll B. Hartline, Scott H. James, Oleksandr Kobzar, Vasyl Kovalishyn, Andriy Vovk, and Volodymyr Brovarets

V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Science of Ukraine, Kyiv, Ukraine

E-mail: brovarets@bpci.kiev.ua

Received: 15 December 2022  Accepted: 15 August 2023

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.

Keywords: Antiviral activity; 4-Iminohydantoin sulfamide derivatives; Docking; Human cytomegalovirus (HCMV)

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-03038-1

Chemical Papers 78 (1) 133–140 (2024)