Brovarets, V. S.

Hodyna, D. M.

Kachaeva, M. V.

Kovalishyn, V. V.

Pilyo, S. G.

Severin, O. O.

Zhytomyr State University Library

 109  IN SILICO STUDY AND IN VITRO ACTIVITY OF NOVEL OXAZOLE DERIVATIVES AGAINST HUMAN CYTOMEGALOVIRUS Severin O.O., Kachaeva M.V., Hodyna D.M., Kovalishyn V.V., Pilyo S.G., Brovarets V.S. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, oleksandrseverin.chem@gmail.com  Human cytomegalovirus (HCMV) is a ubiquitous pathogen affected humans with impaired or immature immune-defence functions [1-3]. Since HCMV infects approximately 60% of people in the developed world and over 99% in developing countries, the risk of morbidity due to HCMV disease is a significant problem for public health [4]. At present, there are several anti-HCMV drugs (Ganciclovir, Valganciclovir, Cidofovir, Maribavir, Letermovir), however, these ones have poor bioavailability and many shortcomings, including associated toxicities, and the emergence of drug resistant viruses [5,6]. Hence, this warrants the need for urgent development of novel antiviral substances.  1,3-Oxazole derivatives are among the most useful heterocyclic compounds from both synthetic and medicinal chemistry aspects [7]. Recently, we have synthesized novel 1,3-oxazole-4-carboxylates and 1,3-oxazole-4-carbonitriles and their antiviral activities against the human cytomegalovirus (HCMV) were evaluated in vitro. These compounds exhibited considerably higher antiviral activity (EC50: < 0.05 μM) against a normal laboratory HCMV strain (AD-169) than Ganciclovir (EC50 = 0.32 μM), an anti-HCMV agent in clinical use. Additionally, the HCMV resistant isolate (GDGr K17) was tested for sensitivity to 1,3-oxazole derivatives with most antiviral potency against the strain AD169. A one of them (5-((2-hydroxyethyl)(methyl)amino)-2-(4-methylphenyl)-1,3-oxazole-4-carbonitrile) showed very high potency (EC50: < 0.05; CC50: >150 µM and SI50 = 3125) towards the resistant isolate compared to standard drugs Cidofovir (EC50 = 0.10 µM, CC50: >30 µM and SI50:<4) [8]. These data indicate that 1,3-oxazole derivatives are promising compounds in the search for design of new anti-HCMV drugs.  In this work, in order for subsequent investigation of antiviral activity of novel 1,3-oxazole derivatives we applied the machine learning technic. The prediction of the antiviral activity of the 1,3-oxazole derivatives against HCV was performed using the Online Chemical Modeling Environment (OCHEM). The predictive QSAR model was created by Transformer-CNNi method [9]. The data set consisted of 671 compounds with antiviral activity obtained from multiple publications and uploaded into the OCHEM. The EC50 values of the molecules in μM were converted into the -log(M) and used as the target variable to develop regression model. The 5-fold cross-validation method was used to evaluate the accuracy of the QSAR model. The optimized parameters setting of machine-learning method was used provided by OCHEM platform. The main statistical parameters of the created QSAR model such as the coefficient of determination (q2) and the mean absolute error (MAE) were 0.71±0.03 and 0.43±0.02 respectively that demonstrated high accuracy and robustness for prediction of the antiviral activity. A set of novel 2-aryl-4-cyano-5-amino-1,3-oxazoles and 1,3-oxazole-5-sulfonylamides as potential anti-HMСV agents generated and screened using the QSAR model were synthesized in V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine and evaluated in vitro. The antiviral activity of the compounds 1 and 2 was predicted as 4.6 -log(M) unit, while the activity of the rest compounds was predicted in the range of 3.8-4.0 -log(M) units.  The all cytotoxicity and efficacy tests performed at UAB. The evaluation was carried out under the auspices of the National Institute of Allergy and Infectious Diseases (USA) and its Collaborative Antiviral Testing Group. The effects of the 1,3-oxazole derivatives on antiviral activity against a normal laboratory HCMV strain, AD-169, and their cytotoxicity was evaluated on HFF cells using CellTiter-Glo (Cytopathic effect/Toxicity) assay (Table 1).   110  Table 1  The antiviral activity and cytotoxicity of the 1,3-oxazole derivatives against AD169 strain of HCMV, in HFF cell line. Compound concentrations are in µM.  No Compound Strain AD169 EC50 CC50 SI50 1 ONCNMeNO NNOMe 0.77 >150 >196 2 ONCNMeNO NN  5.33 >150 >28 Ganciclovir 0.75 >150 >201 3 ONSOOCNNMeONMeNCF   >30 85.52 <3 4 ONSOOCNNMeONMeNCCl   >30 64.18 <2 5 ONNCNN SOOONOMeOMe   >150 >150 1 6 ONSOOCNNMeN SOOCl  >150 >150 1 7 ONCNSON N SOOONNCOMe   >6 21.47 <4 8 ONCNSON N SOOONNCOMeMe >30 115.65 <4 9 ONCNSON N SOOONNCO >30 63.25 <2 Ganciclovir 1.54 >150 >97   111  Control and drug concentrations ranges are 0.048-150 μM. Vehicle is DMSO. EC50 and CC50 are compound concentrations that reduce viral replication and cell viability, respectively, by 50% in CellTiter-Glo (Cytopathic effect/Toxicity) assay. Selectivity Index (SI50) is calculated as the CC50 value divided by the EC50 value.  Compounds exhibited different antiviral activity against the HCMV strain AD169 and, with the exception of 1, 2 and 7, had EC50 values of >30 µM. Compound 1 showed the best activity with EC50 = 0.77 μM which appeared to be similar to control drug Ganciclovir (EC50 = 0.75 μM). Compounds 3, 4, 8 and 9 have shown the identical moderate antiviral activity.  Thus, only 5-amino-4-cyanooxazoles 1 and 2 with oxadiazole moiety displayed the mild biological activity among the series of 5-amino-1,3-oxazole-4-carbonitriles that was also confirmed by the QSAR model predictions. Among sulfonylamide derivatives 3-9 compound 7 showed the best result with EC50 values of >6 µM however it was lower compared to control drug. These results provided evidence that derivatives of 1,3-oxazole could be useful for developing new anti-HCMV drugs.  Acknowledgements This work was supported 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").  1. Collins-McMillen D., Buehler J., Peppenelli M., Goodrum F. Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation // Viruses. – 2018. – 10, ғ 8. – E444. 2. Li X., Huang Y., Xu Z., Zhang R., Liu X., Li Y., Mao P. Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis // BMC Infect. Dis. – 2018. – 18, ғ 1. – Р. 289. 3. Yong M.K., Lewin S.R., Manuel O. Immune Monitoring for CMV in Transplantation // Curr Infect Dis. Rep. – 2018. – 20, ғ 4. – Р. 4. 4. Griffiths P., Baraniak I., Reeves M. The pathogenesis of human cytomegalovirus // J. Pathol. – 2015. – 235. – 2. – Р. 288–297. 5. Ahmed A. Antiviral Treatment of Cytomegalovirus Infection // Infect. Disord. Drug Targets. – 2011. – 11, ғ 5. – Р. 475–503. 6. Frange P., Leruez-Ville M. Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections // Med. Mal. Infect. – 2018. – 48, ғ 8. – Р. 495–502. 7. Zhang H.Z., Zhao Z.L., Zhou C.H. Recent advance in oxazole-based medicinal chemistry // Eur. J. Med. Chem. – 2018. – 144. – Р. 444–492. 8. Kachaeva M.V., Pilyo S.G., Hartline C.B. et al. In vitro activity of novel derivatives of 1,3-oxazole-4-carboxylate and 1,3-oxazole-4-carbonitrile against human cytomegalovirus // Med. Chem. Res. –  2019. – 28. – Р. 1205–1211.  9. https://arxiv.org/abs/1911.06603   

In silico study and in vitro activity of novel oxazole derivatives against human cytomegalovirus

http://eprints.zu.edu.ua/34964/1/%D0%90%D0%97%D0%A5_2022-110-112.pdf

In silico study and in vitro activity of novel oxazole derivatives against human cytomegalovirus

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