Discovery of 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea as a promising anticancer drug via synthesis, characterization, biological screening, and computational studies (original) (raw)
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Cancer and different types of tumors are still the most resistant diseases to available therapeutic agents. Finding a highly effective anticancer drug is the first target and concern of thousands of drug designers. In our attempts to address this concern, a new pyrazine derivative, 1-(5-bromopyrazin-2yl)-1-[3-(trifuoromethyl)benzyl]urea (BPU), was designed via structural optimization and synthesized to investigate its anticancer/antitumor potential. The in-vitro anticancer properties of BPU were evaluated by MTT assay using selected cell lines, including the Jurkat, HeLa, and MCF-7 cells. The Jurkat cells were chosen to study the effect of BPU on cell cycle analysis using fow cytometry technique. BPU exhibited an effective cytotoxic ability in all the three cell lines assessed. It was found to be more prominent with the Jurkat cell line (IC 50 = 4.64 ± 0.08 µM). When it was subjected to cell cycle analysis, this compound effectively arrested cell cycle progression in the sub-G1 phase. Upon evaluating the antiangiogenic potential of BPU via the in-vivo/ex-vivo shell-less chick chorioallantoic membrane (CAM) assays, the compound demonstrated very significant findings, revealing a complementary supportive action for the compound to act as a potent anticancer agent through inhibiting blood vessel formation in tumor tissues. Moreover, the docking energy of BPU computationally scored − 9.0 kcal/mol with the human matrix metalloproteinase 2 (MMP-2) and − 7.8 kcal/mol with the human matrix metalloproteinase 9 (MMP-9), denoting promising binding results as compared to the existing drugs for cancer therapy. The molecular dynamics (MD) simulation outcomes showed that BPU could effectively bind to the previously-proposed catalytic sites of both MMP-2 and MMP-9 enzymes with relatively stable statuses and good inhibitory binding abilities and parameters. Our findings suggest that the compound BPU could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in-vitro and in-vivo investigations. In addition, the current results can be extensively validated by conducting wet-lab analysis so as to develop novel and better derivatives of BPU for cancer therapy with much less side effects and higher activities.
1-(Benzoyloxy)urea and its derivatives were synthesized by modified Scotten-Bauman reaction with adding benzoyl chloride or homologs to hydroxyurea in tetrahydrofuran. Structure characterization was conducted based on ultra-violet (UV-VIS) spectrum, infrared (FT-IR), H nucleus magnetic resonance ( 1 H NMR), C nuclear magnetic resonance ( 13 C NMR) and mass spectrometry (MS). In silico test to predict anti-cancer activity of 1-(benzoyloxy)urea and its derivatives in ribonucleotide reductase enzyme (PDB: 2EUD) was done using Molegro Program. The anti-cancer activity test was performed in vitroby using MTT method to HeLa cell lines. In silico test result (Rerank Score) was correlated relative to anti-cancer activity (log1/IC 50 ). There was a significant linear relationship between in vitroand in silico anti-cancer activity.
Urea-based anticancer agents. Exploring 100-years of research with an eye to the future
Frontiers in Chemistry
Suramin was the first urea-based drug to be approved in clinic, and in the following century a number of milestone drugs based on this scaffold were developed. Indeed, urea soon became a privileged scaffold in medicinal chemistry for its capability to establish a peculiar network of drug−target interactions, for its physicochemical properties that are useful for tuning the druggability of the new chemical entities, and for its structural and synthetic versatility that opened the door to numerous drug design possibilities. In this review, we highlight the relevance of the urea moiety in the medicinal chemistry scenario of anticancer drugs with a special focus on the kinase inhibitors for which this scaffold represented and still represents a pivotal pharmacophoric feature. A general outlook on the approved drugs, recent patents, and current research in this field is herein provided, and the role of the urea moiety in the drug discovery process is discussed form a medicinal chemistry ...
Molecules, 2021
The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N’-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC50 for MCF7 and PC3 cell lines were even less than 3 μM.
European Journal of Medicinal Chemistry, 2012
a b s t r a c t A series of new synthesized N-bis(trifluoromethyl)alkyl-N'-substituted ureas have been tested in the National Cancer Institute (NCI, Bethesda, USA) by Program NCI-60 DTP Human Tumor Cell Line Screen at a single high dose (10 À5 M). COMPARE analysis has been carried out for all tested compounds. The tested compounds showed antitumor activity against individual cell lines. The most sensitive cell lines relative to the tested compounds are: 5g Leukemia RPMI-8226 (GI% 52.7), Non-Small Cell Lung cancer HOP-92 (GI % 88.53), NCI-H522 (GI % 64.41), Melanoma UACC-62 (GI% 53.08), SK-MEL-5 (GI % 74.63), Breast cancer MDA-MB-468 (GI% 51.29), T-47D (GI % 65.1), 5b Leukemia K-562 (GI % 55.55), 7m Leukemia HL-60(TB) (GI % 51.76).
Journal of Enzyme Inhibition and Medicinal Chemistry, 2011
2D and 3D quantitative structure-activity relationship studies have been carried out for establishing a correlation between the structural properties of benzyl urea derivatives and their anti-tumour activities. From this correlation, the new chemical entities were designed, and their activity and absorption, distribution, metabolism, excretion, and toxicity properties were also predicted. Finally, the most promising compounds from these screening were synthesized and biologically evaluated for their anti-cancer properties. Compound 1-(2, 4-dimethylphenyl)-3, 3-dimethyl-1-(2-nitrobenzyl) urea (7d) showed significant anti-proliferative activity (at 100 µg/mL) in human cancer cell lines-T-cell leukemia (Jurkat J6), myelogenous leukemia (K562), and breast cancer (MCF-7) compared to reference standard 5-flurouracil.
Synthesis, enzyme inhibition and anticancer investigation of unsymmetrical 1,3-disubstituted ureas
Journal of the Serbian Chemical Society, 2014
In this research work seventeen urea derivatives, including five new derivatives N-mesityl-N'-(3-methylphenyl)urea (2), N-(3-methoxyphenyl)-N'-(3-methylphenyl)urea (4), N-mesityl-N'-(4-methylphenyl)urea (6), N-(1,3-benzothiazol-2-yl)-N'-(3-methylphenyl)urea (9) and N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) have synthesized by reacting ortho, meta and para tolyl isocyanate with primary and secondary amines by previously reported method. We exhibited all series (1-17) to urease, ?-glucuronidase and snake venom phosphodiesterase enzyme inhibition assays. The ranges of % inhibition for urease, ?-glucuronidase and phosphodiesterase enzymes were 0.3-45.3, 4.9-44.9 and 1.2-46.4 % respectively. Moreover, the effect of these compounds on prostate cancer cell lines was also observed. The new compound N-(1,3-benzothiazol-2-yl)-N'-(3-methylphenyl)urea (9) showed in vitro anticancer activity with IC50 value of 78.28 ? 1.2 ?M. All the compounds were characterized ...