Diaryl Urea Derivatives Research Articles

Design, synthesis and in vitro antitumor evaluation of novel diaryl urea derivatives bearing sulfonamide moiety

A novel series of diaryl urea derivatives bearing sulfonamide moiety have been designed and synthesized. Their in vitro antitumor effect against human cancer cell lines MX-1, A375, HepG2, Ketr3 and HT-29 was screened and evaluated by the standard MTT assay with sorafenib as the positive control. Some of the compounds showed significant inhibitory activity against multiple cell lines compared to sorafenib. In particular, 2,6-dimethyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]naphthalen-2-yl}sulfonyl morpholine (10d) was found to be the most potent against A375, HepG2 and Ketr3 with IC50 values of 0.65–0.97 μmol/L, which were 5–20-fold more potent than sorafenib. Compound 10d emerged as a valuable lead for further optimization.

Optimization of the Reaction Conditions for Synthesis of 3-(Aryloxy)quinoline Derivatives via Friedländer's Cyclization Reaction

6,7-Dimethoxy-2-methyl-3-(4-nitrophenoxy)quinoline was synthesized by Friedlander's cyclization reaction. Different bases and solvents were tested in order to optimize the reaction conditions. The highest yields were obtained using piperidine in refluxing ethanol. Further reactions were carried out in order to prepare different diarylamide and diarylurea derivatives in moderate to high yields in order to examine their anticancer activities. Herein, we optimized the optimum reaction conditions to synthesize 3-(aryloxy)quinoline derivatives in terms of higher yield and by avoiding lengthy workup and column puri- fication. Our optimized reaction conditions can be applied to scale up to large scales with simple isolation of the pure product. In the present investigation, we report the optimized reaction conditions for preparation of 3-aryloxy- quinoline via Friedlander's cyclization, followed by synthesis of diarylurea and diarylamide derivatives possessing quino- line nucleus. Results and Discussion Herein we report an efficient method for the synthesis of novel quinoline derivatives via the Friedlander's reaction through condensation of dimethoxy substituted o-amino- benzaldehyde with a ketone, 1-(4-nitrophenoxy)propan-2- one (2), in the presence of different bases and solvents. Among all the bases tested, piperidine was found to be the Table 1. Optimization of Friedlander's cyclization reaction condition using different bases and solvents

A Simple and Efficient Synthesis of Diaryl Ureas with Reduction of the Intermediate Isocyanate by Triethylamine

Thirty symmetrical diaryl urea derivatives were synthesised in moderate to excellent yields from arylamine and triphosgene with triethylamine as a reducing agent for the intermediate, isocyanate. It was significant that part of the products could be collected in almost quantitative yield without column chromatography. The procedure under mild reaction conditions was tolerant of a wide range of functional groups. The structures of the compounds were determined by NMR, MS and X-ray crystallographic analyses.

Abstract 2599: Inhibitory effects of new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on AP-1 activity and neoplastic cell transformation induced by insulin-like growth factor 1.

Abstract Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine scaffold. In this study, we demonstrate that a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c-jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Taken together, these results indicate that a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway. Citation Format: Hyo Jeong Yun, Hong Seok Choi. Inhibitory effects of new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on AP-1 activity and neoplastic cell transformation induced by insulin-like growth factor 1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2599. doi:10.1158/1538-7445.AM2013-2599 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Synthesis and in vitro antitumor activity of novel diaryl urea derivatives

Abstract A series of novel diaryl ureas containing 4-[(2-amino-6-trifluromethyl)pyrimidine-4-yl]piperazine-1-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib, some compounds showed more potent and a broader spectrum of anti-cancer activities. Among them, compound 2p demonstrated significant inhibitory activities against MDA-MB-231, HT-29 and MCF-7 cell lines with IC 50 values of 0.016, 0.63, 0.001 μmol/L, respectively.

Discovery of Hybrid Dual N-Acylhydrazone and Diaryl Urea Derivatives as Potent Antitumor Agents: Design, Synthesis and Cytotoxicity Evaluation

Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications.

Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.

Synthesis and carbonic anhydrase inhibitory properties of novel 1,4-dihydropyrimidinone substituted diarylureas

A new series of 1,4-dihydropyrimidinone (DHPM) substituted diaryl urea and thiourea derivatives were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and II were evaluated. 4-Nitrophenyl-1,4-DHPM was prepared with dimedone, nitrobenzaldehyde and urea or thiourea and nitro group was reduced to amine derivative. The compound was reacted with isocyanates and isothiocyanates to get the final products. The results showed that all the synthesized compounds inhibited the carbonic anhydrase isoenzyme activity; 4c (IC50 = 66.23 µM for hCA I) and 4f (IC50 = 63.09 µM for hCA II) have the most inhibitory effect. The synthesized compounds are very bulky to be able to bind near the zinc ion and they much more probably bind as the coumarins and activators.

ChemInform Abstract: Design, Synthesis and Anticancer Activities of Diaryl Urea Derivatives Bearing N‐Acylhydrazone Moiety.

AbstractThe title compounds (I), (II) are screened for their in vitro cytotoxic activities against some human cell lines, A549, MDA‐MB‐231, HL‐60.

Synthesis and cytotoxic activity of diaryl urea derivatives with a 4-methylpiperazinylcarbonyl moiety

Eleven diarylurea derivatives (1a–1k) bearing N-methylpiperazinyl moiety were synthesized by the reaction of isocyanate with arylamine. The structures of 1a–1k were characterized by 1H-NMR and MS. The cytotoxic activities of 1a–1k were evaluated via MTT method against human lung adenocarcinoma epithelial cell line A549 and human prostate carcinoma cell line PC3. Compounds 1d and 1k displayed potent cytotoxic activity. The results suggested that the activities are considerably related to the substituent group at another phenyl ring.

Design, synthesis and antiproliferative activities of diaryl urea derivatives bearing N-acylhydrazone moiety

Abstract A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their antiproliferative activities against human leukemia cell line (HL-60), human lung adenocarcinoma epithelial cell line (A549) and human breast cancer cell line (MDA-MB-231) in vitro by standard MTT assay. The pharmacological results indicated that some compounds exhibited promising antitumor activities. Compound 1j showed the most potent antiproliferative activity against the tested three cell lines with IC50 values of 0.13 μmol/L, 0.7 μmol/L and 0.5 μmol/L, respectively.

Design and Synthesis of an Anticancer Diarylurea Derivative with Multiple-Kinase Inhibitory Effect

A diarylurea compound 1 possessing pyrrolo[3,2-<TEX>$c$</TEX>]pyridine nucleus was designed and synthesized with structure similarity to Sorafenib. Compound 1 was tested over 60-cancer cell line panel at a single dose concentration of 10 <TEX>${\mu}M$</TEX> and showed high activity. It was further tested in a five-dose mode to determine its <TEX>$IC_{50}$</TEX>, TGI, and <TEX>$LC_{50}$</TEX> values over the 60 cell lines. Compound 1 showed high potency and good efficacy, and was accordingly tested at a single dose concentration of 10 <TEX>${\mu}M$</TEX> over a panel of 40 kinases. At this concentration, it completely inhibited the enzymatic activities of a number of oncogenic kinases, including ABL, ALK, c-RAF, FLT3, KDR, and TrkB. The target compound was subsequently tested over these 6 kinases in 10-dose testing mode in order to determine its <TEX>$IC_{50}$</TEX> values.

ChemInform Abstract: Catalytic Oxidative Carbonylation of Arylamines to Ureas with W(CO)6/I2 as Catalyst.

AbstractTitle carbonylation reaction of a wide variety of aromatic amines (I) with carbon monoxide is smoothly achieved in the system iodine—DMAP—W(CO)6 to give symmetrical diarylurea derivatives (III).

Design, Synthesis and Anticancer Activities of Diaryl Urea Derivatives Bearing &lt;i&gt;N&lt;/i&gt;-Acylhydrazone Moiety

A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their cytotoxic activities in vitro against human lung adenocarcinoma epithelial cell line (A549), human breast cancer cell line (MDA-MB-231) and human leukemia cell line (HL-60) by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Several compounds (1a, 1f and 1h) were further evaluated against human embryonic fibroblast, lung-derived cell line (WI38). The pharmacological results indicated that some compounds exhibited promising anticancer activities. In particular, compound 1f showed the most potent cytotoxicity against the tested three cell lines with IC(50) values of 0.41 µM, 0.24 µM and 0.23 µM, respectively.

Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido[1,2‐a]pyrimidin‐4‐one Group

We herein disclose a series of novel diaryl urea derivatives possessing a 4H-pyrido[1,2-a]pyrimidin-4-one group as novel potent anticancer compounds. The structures were confirmed by IR,(1)H-NMR, and MS. All the compounds were screened for their antiproliferative activity against the human breast cancer cell line (MDA-MB-231). The pharmacological results indicated that most of the compounds showed moderate activity. The best of this series is compound 4c (IC(50)= 0.7 micromol/L), with a potency 3.6-fold higher than Sorafenib (IC(50) = 2.5 micromol/L), which was approved in 2005.

Hydrogen Bonding Is Not Everything: Extensive Polymorphism in a System with Conserved Hydrogen Bonded Synthons

A simple N,N′-diaryl urea derivative was found to form four different anhydrous crystal forms (I−IV°), which can be crystallized in pure form by several techniques from solution as well as from the melt. These polymorphs were characterized by thermomicroscopy, differential scanning calorimetry, Fourier-transform infrared spectroscopy and single crystal and powder X-ray diffraction. The polymorphs were found to be purely monotropically related with large differences in their heats of fusion (11.1 kJ mol−1 for the least stable form I, 34.5 kJ mol−1 for the most stable form IV°). The crystal structures of all forms show the same conformer for forms I−III and a second conformer in form IV°. However, the hydrogen bonding motifs in all of the polymorphs are the same and thus the compound can be seen as a model for the importance of the entire crystal packing arrangement to the overall energy and stability of the crystal form, as opposed to just a few dominant interactions.

3D-QSAR Studies of Various Diaryl Urea Derivatives of Multi-targeted Receptor Tyrosine Kinase Inhibitors: Molecular Field Analysis Approach

3D-QSAR analysis has been performed on a series of diaryl urea derivatives of multi-targeted receptor tyrosine kinase inhibitors. Models were developed using the most widely used computational approach molecular field analysis (MFA) from our dataset for the KDR, cKit and FLT3 inhibitors using genetic partial least square (G/PLS) method. These models showed excellent internal predictability and consistency and validation using test set compounds yielded a good predictive power for the activity values of three set of inhibitors. These models would offer utility in guiding the rational design of multi-targeted KDR, cKit and FLT3 receptor tyrosine kinase inhibitors for therapeutic applications. Keywords: QSAR, Receptor tyrosine kinase, MFA, Molecular field analysis, Genetic partial least squares (G/PLS) method

INVESTIGATION ON SOME REACTIONS OF SACCHARINYL BENZOIC ACID AZIDES

Saccharinyl benzoic acid azides 2a-c were used to synthesize a number of noncondensed heterocyclic systems. Thus azides 2a or 2c reacted with glycine to give 1,3-oxazolin-5-one derivatives 3a and 3b. However azide 2b reacted to give diaryl urea derivative which was easily cyclized to give imidazol -2,5- dione (6). Also azides 2a-c reacted with glycolic acid to give 1,3-oxazolin -2,5-dione derivatives (7a-c) and with aroyl hydrazines to give the corresponding hydrazides (8a-f) which were cyclized to 1,3,5-oxadiazole derivatives (9a-f).