„IN SILICO“ PREDICTION OF PHARMACOKINETIC PROPERTIES AND DRUGLIKENESS OF NOVEL THIOUREA DERIVATIVES OF NAPROXEN

1st International Conference on Chemo and BioInformatics, ICCBIKG  2021, (371-374)

AUTHOR(S) / АУТОР(И): Nikola V. Nedeljković, Vladimir D. Dobričić, Marina Ž. Mijajlović, Gordana P. Radić, Miloš V. Nikolić, Ana S. Stanković, Zorica B. Vujić

E-ADRESS / Е-АДРЕСА: nikolaned95@gmail.com, marina.mijajlovic@medf.kg.ac.rs,
vasic_gordana@yahoo.com, milos.nikolic@medf.kg.ac.rs, ana_stankovic@outlook.com, vladimir.dobricic@pharmacy.bg.ac.rs, zorica.vujic@pharmacy.bg.ac.rs

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DOI: 10.46793/ICCBI21.371N

ABSTRACT / САЖЕТАК:

Masking the carboxyl group of naproxen with other functional groups may be a promising strategy to decrease its gastrointestinal toxicity. Thiourea moiety has been described as an important pharmacophore in a variety of pharmacologically active compounds, including anti-inflammatory, antiviral, anticancer, hypoglycemic and antimicrobial agents. Our research group has previously designed twenty novel thiourea derivatives of naproxen, containing amino acids (glycine, L-alanine, β-alanine, L-valine and L-phenylalanine – compounds 1,2,3,4 and 5, respectively), their methyl (6–10) and ethyl esters (11–15), as well as aromatic amines (16–20). Pharmacokinetic properties and druglikeness of these compounds were predicted using SwissADME web tool (http://www.swissadme.ch/). Predicted pharmacokinetic properties include potential for gastrointestinal absorption, blood-brain barrier permeability, skin permeability, transport mediated by P-glycoproteins and enzyme inhibitory potential. Druglikeness was evaluated using Lipinski’s, Ghose’s, Veber’s, Egan’s and Muegge’s rules, as well as on the basis of bioavailability score. All tested compounds had high-predicted gastrointestinal absorption and low blood-brain barrier permeability. Also, derivatives 2, 4, 7, 9, 10, 12, 14, 15 and 18 were predicted to be substrates for P-glycoprotein. Derivatives with aromatic amines (16–20) showed inhibitory potential against all tested CYP isoforms. Derivative 19 had the highest, while derivative 13 demonstrated the lowest predicted skin permeability. Finally, derivatives 1–12, except 5 and 10, have druglike structures, since they obey to all imposed rules.

KEY WORDS / КЉУЧНЕ РЕЧИ:

naproxen, thiourea derivatives, pharmacokinetic properties, druglikeness, SwissADME.

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