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Predicting of ADMET Properties and Correlation Studies in a Series of Cyclic and Acyclic Urea Derivatives

In the course of our work, a diverse cyclic and acyclic urea derivatives were synthesized and tested on cell viability on human acute monocytic leukemia THP-1 and human acute T cell leukemia Jurkat cell lines, as well as on the antibacterial activity against three E. coli strains, i.e., a strain susceptible to antibiotics, a strain resistant to macrolide antibiotics and a strain resistant to aminoglycoside antibiotics (BL21(DE3)/pET25b(+)-sgm (F- ompT hsdSB(rB-mB-)gal dcm (DE3)). [1] In this work, the structural features of synthesized urea derivatives (n = 17) and the impact of different substituents on their physico-chemical, biological and toxicological properties were analyzed in correlation studies using molecular descriptors (MlogP, Mr, TPSA, V and 13C NMR /ppm), drug-likeness scores computed for GPCR ligand (GPCR l-dls), ion channel modulator (ICM-dls), kinase inhibitor (KI-dls), nuclear receptor ligand (NRL-dls), protease inhibitor (PI-dls) and enzyme inhibitor (EI-dls), as well as for different ADMET parameters. Molecular descriptors were calculated using Molinspiration property engine v2011.04 and Molinspiration bioactivity score v2011.06. The ADMET properties were computed by MedChem StudioTM and ADMET PredictorTM 6.0 (Simulations Plus, Inc., USA). All analyses were performed using OriginPro 8.0 software (Origin Laboratories, USA). Negative and non significant drug-likeness scores were computed for most investigated compounds, except for EI-dls of N1-benzyloxy- and N1-hydroxy-N2-p-(carboxylic acid)phenyl urea (6 and 12), N1, N2, N3-trihydroxybiuret (14) and 1-(N-benzyloxycarbamoyl)benzotriazole (1) (EI-dls 0.21 – 0.31). Interestingly, these compounds were also the most active compounds across the various biological tests. The results of the correlation studies revealed the following correlations: Mr vs. V, r = 0.977, y = 0.907x - 14.102 ; Mr vs. GPCR dls, r = -13.769(-x/65.269) + 0.178 ; MLogP vs. TOX hERG, r = 0.895, y = - 6.009(-x/6.777) + 8.285 ; MlogP vs. EI dls, r = 0.822, y = - 0.003(-x/0.217) + 0.123 ; MlogP vs. Mr, r = 0.816, y = 47.407x + 155.846 ; MlogP vs. TOX ATTP, r = 0.755x + 0.561 ; MlogP vs. TOX DM, r = 0.721, y = 3.509x - 0.442. According to ADMET Predictor analyses, these compounds are mostly CYP 2E1 and CYP 1A2 substrates and CYP 1A2 inhibitors. For investigated compounds the following ADMET parameters were also predicted: ADMET risk between 1.0 - 7.0, CYP risk 0.0 - 2.0 and TOX risk between 1.0 - 5.0. Reference 1. Kos I†, Jadrijevic-Mladar Takac M, Butula I†, Birus M, Maravic-Vlahovicek G, Dabelic S. Synthesis, antibacterial and cytotoxic activity evaluation of hydroxyurea derivatives. Acta Pharm 2013 ; 63(2), 174-190, DOI: 10.2478/acph-2013-0014.

Cyclic and acyclic ureas; ADMET properties; molecular descriptors; drug-likeness; correlation studies

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