Synthesis, antimicrobial, anti-cancer and in silico studies of new urea derivatives

• Published in: Bioorganic chemistry Vol. 112; p. 104953
• Main Authors: Sroor, Farid M., Othman, Abdelmageed M., Tantawy, Mohamed A., Mahrous, Karima F., El-Naggar, Mostafa E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2021
• Subjects: Anti-HepG2; Anti-microbial; DNA damage; DNA fragmentation; Gene expression; Molecular docking; Urea derivatives; DNA damage; Anti-microbial; Anti-HepG2; DNA fragmentation; Urea derivatives; Gene expression; Molecular docking
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104953

Series of alkyl- and aryl- urea derivatives 5–17 were prepared and evaluated in vitro as antimicrobial and anticancer agents. The reaction of isocyanates with the corresponding amines in acetonitrile afforded the urea derivatives in moderate to excellent yield. The antimicrobial activity of the prepared compounds 5–17 were tested against E. coli, S. aureus, and C. albicans and the compounds 5 and 8 recorded the highest activity at the MIC level of 0.0489 and 3.13 µM respectively. The anti-cancer activity of the synthesized compounds were evaluated against HepG2 and the compounds 5 and 7 exhibited the most active compound at IC50 4.29 and 5.48 µM compared to 5 flurouracil with IC50=316.25 µM.
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•Synthesizing of some new alkyl- and aryl urea derivatives in facile method.•The prepared urea derivatives have been tested against microbial strains E. coli, S. aureus, and C. albicans.•Anti-cancer activity against HepG2 was determined.•Most of the prepared urea derivatives were found to be more active than Florouracil (5-FU) drug.•The compound 5 was found as the most active compound against as antimicrobial and anti-HepG2 agents.
The reaction of an alkyl or aryl isocyanates with some primary amines in acetonitrile at room temperature afforded the corresponding alkyl- and aryl-urea derivatives. All the prepared urea compounds have been elucidated by FTIR, NMR, and elemental analysis. The compounds 1 and 3 were confirmed by single-crystal X-ray diffraction. The 4-tolylsulfonyl isocyanate reacted with the aryl amines 1, 2, 3, and 2,4-dichloroaniline to afford the corresponding sulfonylurea derivatives 5–8. Likewise, the reaction of the isocyanates with 2,4-dichloroaniline, 5-methyl isoxazole-3-amine, and 2-aminothiazole derivatives gave the corresponding urea derivatives 9–17. All the prepared compounds 5–17 were tested in vitro as anti-microbial and anti-HepG2 agents. Moreover, analyzing gene expression of TP53-exon4 and TP53-exon7, DNA damage values, and DNA fragmentation percentages have been discussed. The compounds 5 and 8 recorded the highest activity against the tested microbial strains with maximum activity against C. albicans (50 mm) and B. mycoides (40 mm), respectively. The compounds 5 inhibited the growth of E. coli, S. aureus, and C. Albicans at the MIC level of 0.0489 µM, while the compound 8 was able to inhibit the visible growth of E. coli and C. albicans at MIC value of 3.13 µM and S. aureus at 0.3912 µM. In the same line, compound 5 showed the best cytotoxic activity against the HepG2 cell line (IC50 = 4.25 µM) compared to 5 fluorouracil with IC50 = 316.25 µM. Expression analysis of liver cancer related to a gene including TP53-exon4 and TP53-exon7 was used in HepG2 Liver cancer cell lines using RT-qPCR. The expression values of TP53-exon4 and TP53-exon7 genes were decreased. The DNA damage values and DNA fragmentation percentages were increased significantly (P < 0.01) in the treated HepG2 (5) sample compared with the negative control. Docking studies were performed for the synthetic compounds against 2 bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics, and one cell division protein kinase 2 (CDK2) as target for anticancer drugs.