engleski

Evaluation of Substituted Ureas Potential Toxicity by Correlation Studies Using Topological Indices, Molecular Descriptors and ADMET Parameters

The potential toxicity of several cyclic and acyclic urea derivatives were evaluated in correlation studies using topological indices, molecular descriptors and ADMET toxicological parameters. Urea derivatives (n=17) were synthesized in our labs 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 (strains susceptible to antibiotics and resistant to macrolide and aminoglycoside antibiotics). (1) Topological indices (TIs) were calculated by the software DRAGON 6.0, molecular descriptors (MDs) and ADMET parameters were predicted by MedChem StudioTM and ADMET PredictorTM 6.0 (Simulations Plus, Inc., USA). All analyses were performed using OriginPro 8.0 software (Origin Laboratories, USA). Out of 16 indices used in these studies the best correlations were obtained with: Wiener number (W), Randić number (CID), Randić connectivity index (X1) and information index (ISIZ) with molecular descriptors (Sv – sum of the van der Waals volume scaled on C, Mr - relative molecular mass and MLog P – lipophilicity). The following correlations were obtained: W vs Mr (R = 0.9464), ISIZ vs MLog P (0.7926), X1 vs MLog P (R = 0.7825), CID vs MLog P (R = 0.7797), Mr vs MLogP (R = 0.8761) and MLog P vs Sv (R = 0.8491). The best linear correlation was obtained between ISIZ and TOX hERG scores (R = 0.8170) while correlations of TIs and MDs with metabolic activity on THP 1 or Jurkat cell lines were of less significance. Parameters, predicted for these compounds by ADMET analyses, are: ADMET risk between 1.0 - 7.0, CYP risk 0.0 - 2.0 and TOX risk between 1.0 - 5.0. Topological indices (W, CID, X1 and ISIZ) were successfully used in correlation studies with molecular descriptors (MDs) and ADMET parameters in a series of substituted urea derivatives. For compounds with the most significant metabolic activity either on THP 1 or Jurkat cell line (N-hidroxy- and N, N’-bisbenzyloxy-urea, N-hydroxy-, N, N’, N’’-tribenzyloxy- and N, N’, N’’-trihydroxy-biuret) the highest scores for their toxicological parameters were revealed.

Urea derivatives; molecular descriptors; topological indices; ADMET; toxicity

nije evidentirano