Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities

2020 ◽  
Vol 20 (3) ◽  
pp. 335-345 ◽  
Author(s):  
Nadia Y. Megally Abdo ◽  
Rafat M. Mohareb ◽  
Waleed N. Al-darkazali
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Ethyl Cyanoacetate ◽  
Structural Diversity ◽  
Cancer Cell Lines ◽  
Wide Range ◽  
High Yields ◽  
Isoxazole Derivatives

Background: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery. Objective: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors. Methods: The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents. Results: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50’s 0.29, 0.68, and 0.42μM, respectively, against the A549 cell line. Conclusion: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

2020 ◽  
Vol 20 (10) ◽  
pp. 1209-1220
Author(s):  
Rafat M. Mohareb ◽  
Ensaf S. Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Proliferative Activity ◽  
Cancer Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Cytotoxic Compounds ◽  
Triazine Derivatives ◽  
Target Molecules

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

scholarly journals Multi-component Reactions of Cyclohexan-1,3-diketones to Produce Fused Pyran Derivatives with Antiproliferative Activities and Tyrosine Kinases and Pim-1 Kinase Inhibitions

2021 ◽  
Vol 68 (1) ◽  
pp. 51-64
Author(s):  
Rafat Milad Mohareb ◽  
Rehab Ali Ibrahim ◽  
Ensaf Sultan Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Ethyl Cyanoacetate ◽  
Cancer Cell Lines ◽  
The Other ◽  
Thiazole Derivatives ◽  
Dione Derivative ◽  
Cytotoxic Compounds ◽  
Antiproliferative Activities

In this work the multi-component reactions of either of the arylhydrazocyclohexan-1,3-dione derivatives 3a–c with either of benzaldehyde (4a), 4-chlorobenzaldehyde (4b) or 4-methoxybenzaldehyde (4c) and either malononitrile (5a) or ethyl cyanoacetate (5b) giving the 5,6,7,8-tetrahydro-4H-chromene derivatives 6a–r, respectively, are presented. The reaction of two equivalents of cyclohexan-1,3-dione with benzaldehyde gave the hexahydro-1H-xanthene-1,8(2H)-dione derivative 7. On the other hand, the multi-component reactions of compound 1 with dimedone and benzaldehyde gave 13. Both of 7 and 13 underwent heterocyclization reactions to produce fused thiophene, pyran and thiazole derivatives. Selected compounds among the synthesized compounds were tested against six cancer cell lines where most of them gave high inhibitions; especially compounds 3b, 3c, 6b, 6c, 6d, 6f, 6i, 6m, 6n, 8b, 14a, 15 and 16 being the most cytotoxic compounds. Further tests against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 6c, 6d, 6f, 6n, 14a and 15 were the most potent of the tested compounds toward the five tyrosine kinases and compounds 3c, 6c, 6d, 6n and 15 displayed the highest inhibitions toward Pim-1 kinase.

Uses of Cyclohexan-1,3-dione for the Synthesis of Thiazole, Pyrazole, Thiophene, Isoxazole and Pyran Derivatives with Antitumor Activities

2020 ◽  
Vol 17 (5) ◽  
pp. 597-609
Author(s):  
Rafat Milad Mohareb ◽  
Nadia Youssef Megally Abdo ◽  
Waleed Nabeel Al-darkazali
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Cancer Cell Lines ◽  
Structural Features ◽  
Active Compounds ◽  
Wide Range ◽  
Heterocyclic Derivatives ◽  
Therapeutic Activities ◽  
High Inhibition

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market. Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Synthesis of Thiazole, Thiophene, Pyran and Pyridine Derivatives Derived from 3-phenyl-1H-pyrazol-5(4H)-one with Anti-proliferative, Tyrosine Kinase and PIM-1 Kinase Inhibitions

2020 ◽  
Vol 17 (4) ◽  
pp. 485-501
Author(s):  
Rafat Milad Mohareb ◽  
Ibram Refat Mikhail
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Cancer Cell Lines ◽  
Structural Features ◽  
Pyrazole Derivatives ◽  
Active Compounds ◽  
Starting Compound ◽  
Wide Range ◽  
Therapeutic Activities

Background: A wide range of pyrazole derivatives gained special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the pyrazole nucleus are known in the market. Methods: The 3-phenyl-1H-pyrazol-5(4H)-one was the key starting compound for many heterocyclic reactions to produce substituted and fused pyrazole derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460 were measured through which compounds showed high inhibitions. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty-nine pyrazole derivatives were synthesized. Nine of them 8b, 9, 12b, 12d, 14b, 15b, 18d, 18f, 19b, and 21d were the most active compounds toward the selected cancer cell lines. Compounds 12b, 14b, 18d, 18f, and 21d showed high inhibitions toward the tyrosine kinases, whereas compounds 14b, 18d, and 18f were the most potent inhibitors of Pim-1.

Design, Synthesis and Biological Evaluation of 3-(3,4,5-Trimethoxyphenyl)- 5-(2-(5-arylbenzo[b]thiophen-3-yl)oxazol-5-yl)isoxazole Derivatives as Anticancer Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 345-351
Author(s):  
Syndla Premalatha ◽  
G. Rambabu ◽  
Islavathu Hatti ◽  
Dittakavi Ramachandran
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Isoxazole Derivatives

A new series of 3-(3,4,5-trimethoxyphenyl)-5-(2-(5-arylbenzo[b]thiophen-3-yl)oxa zol-5- yl)isoxazole derivatives were designed and synthesized. All these derivatives were evaluated for their anticancer activity against various human cancer cell lines such as MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer) and MDA MB-231 (breast cancer)-four human cancer cell lines by using MTT assay. Here, etoposide was used as a standard reference drug and most of the compounds were exhibited good anticancer activity with respect to cell lines. Among all compounds, five compounds 11b, 11c, 11f, 11i and 11j showed more potent activity than standard drug, in which, compound 11f was the most promising compound.

New Approaches for the Synthesis of Fused Thiophene, Pyrazole , Pyran and Pyridine Derivatives with Anti-Proliferative Together with c-Met Kinase and Prostate Cancer Cell Inhibitions

2020 ◽  
Vol 20 ◽  
Author(s):  
Rafat M. Mohareb ◽  
Yara R. Milad ◽  
Reem A. El-Ansary
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Aromatic Aldehydes ◽  
Cancer Cell Lines ◽  
Enzymatic Activities ◽  
Pyridine Derivatives ◽  
Wide Range ◽  
Target Molecules

Background:: Recently multi-component reactions producing pyran and pyridine derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the pyran and pyridine nucleus were known. Objective:: We are aiming in this work to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from cyclohexan-1,3-dione followed by its heterocyclization reactions to produce anticancer target molecules. Methods:: This work demonstrated multi-component reactions of cyclohexan-1,3-dione with aromatic aldehydes and diethylmalonate using triethylamine as a catalyst to give the 7,8-dihydro-4H-chromen-5(6H)-one derivatives 4a-c. The reaction of compounds 4a-c with either of hydrazine hydrate of phenylhydrazine gave the chromeno[2,3-c]pyrazole derivatives 5a-f, respectively. In addition, further heterocyclization reactions were adopted to give the chromeno[3,2-d]isoxazole, chromene-3-carboxamide derivatives. Moreover, the multi-component reaction of cyclohexan-1,3-dione (1) with either of aromatic aldehydes and diethylmalonate using a catalytic amount of ammonium acetate gave the 1,4,5,6,7,8-hexahydroquinoline derivatives 13a-c. The anti-proliferative activities of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 were studied. In addition the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. Results:: Anti-proliferative evaluations, c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured and the results obtained in most cases, indicated that the presence of electronegative Cl group through the molecule favour the inhibitions. Conclusion:: The compounds with high anti-proliferative activity towards the cancer cell lines were 4a, 4b, 6d, 6e, 6f, 10e, 10f, 12c, 14e, 14f, 15c, 16d, 16e, 16f, 19c and 20c. Compounds 4b, 6c, 6d, 8b, 10c, 10d, 12b, 13b, 14c, 14d, 15b, 16c, 16d, 17b, 17c, 19b, 20b and 20c exhibited high potency against c-Met kinase and compounds 4a, 4b, 6b, 6c, 6d, 6f, 8b, 8c, 10c, 10d, 10e, 12b, 12c, 13a, 13b, 13c, 14c, 14d, 14e, 14f, 15b, 15c, 16b, 16c, 16d, 17b, 17c, 19c, 19d, 20a, 20b and 20c displayed high inhibitions toward PC-3 cell line.

Synthesis and antiproliferative and c-Src kinase inhibitory activities of cinnamoyl- and pyranochromen-2-one derivatives

2013 ◽  
Vol 91 (8) ◽  
pp. 741-754 ◽  
Author(s):  
Karam Chand ◽  
Amir Nasrolahi Shirazi ◽  
Preeti Yadav ◽  
Rakesh K. Tiwari ◽  
Meena Kumari ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Human Cancer ◽  
Src Kinase ◽  
Cancer Cell Lines ◽  
Ovarian Adenocarcinoma ◽  
Human Cancer Cell Lines ◽  
Mcf 7

A series of 6- and 8-cinnamoylchromen-2-one and dihydropyranochromen-2-one derivatives were synthesized and their antiproliferative activities were evaluated against three human cancer cell lines, i.e., ovarian adenocarcinoma (SK-OV-3), leukemia (CCRF-CEM), and breast carcinoma (MCF-7). In general, 8-cinnamoylchromen-2-one derivatives were found to have higher antiproliferative activity against the cancer cells when compared with 6-cinnamoyl analogues. Among all of the hybrid chromen-2-one − chalcone/flavanone compounds, a 7-hydroxy-8-cinnamoylchromen-2-one derivative 35 was found to be consistently active against all the cancer cell lines and inhibited the cell proliferation of SK-OV-3, CCRF-CEM, and MCF-7 by 63%, 50%, and 43%, respectively, at a concentration of 50 μmol/L after 72 h of incubation. This compound also exhibited the highest Src kinase inhibition (IC50 = 14.5 μmol/L). Structure−activity relationship studies provided insights for designing the next generation of chromen-2-one − chalcone hybrid prototypes and the development of new leads as anticancer agents and (or) Src kinase inhibitors.

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