Multi-component reactions of cyclohexan-1,3-dione to synthesize heterocyclic derivatives with c-Met enzymatic activity, anti-prostate, anti-proliferative and tyrosine kinase activities

ABSTRACT. 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 aryl hydrazones of cyclohexan-1,3-dione  followed by its heterocyclization reactions to produce anticancer molecules. The multi-component reactions of the arylhydrazocyclohexan-1,3-dione derivatives 3a-c produced the 1,4,5,6,7,8-hexahydroquinoline derivatives 6a-r and the 4,5,6,8-tetrahydrochromeno[2,3-c]pyrazole derivatives 10a-c. Other multi-component reactions were demonstrated. The anti-proliferative activity of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. The results obtained in most cases, indicated that the presence of electronegative Cl group through the molecule favour the inhibitions.                 KEY WORDS: Multi-component reactions, Cyclohexan-1,3-dione, Chromene, Chromeno[2,3-c]pyrazole, Cytotoxicity   Bull. Chem. Soc. Ethiop. 2022, 36(1), 119-136.                                                             DOI: https://dx.doi.org/10.4314/bcse.v36i1.11                                                      &nbsp

Antiproliferative and Antiprostate Cancer Activities of Heterocyclic Compounds Derived from Cyclohexane-1,4-dione

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicity of the synthesized compounds was studied on six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work

Synthesis and anti-tumor evaluation of novel hydrazide-hydrazone derivatives

The reaction of cyclopentanone with cyanoacetylhydrazine gave the 2-cyano-2-cyclopentylideneacetohydrazide (1). Treatment of compound 1 with elemental sulphur in the presence of triethylamine afforded the 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbohydrazide (2) which in-turn formed the corresponding intermediate diazonium salt. The latter was coupled with either ethyl cyanoacetate or ethyl acetoacetate to form the 2-cyano-2-(3-(hydrazinecarbonyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)hydrazono)acetate (3) and ethyl 2-(2-(3-(hydrazinecarbonyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)hydrazono)-3-oxobutanoate (4), respectively. On the other hand, the reaction of compound 1 with either benzaldehyde or acetophenone afforded N\u27-benzylidene-2-cyano-2-cyclopentylideneacetohydrazide (7) and 2-cyano-2-(2-cyclopentylidene)phenylacetohydrazide (10), respectively. Moreover, compound 1 was used to synthesise the 2-cyano-2-cyclopentylidene-N\u27-(arylthiazol-2(3H)-ylidene)acetohydrazides 6a,b, 2-(2-benzylidenecyclopentylidene)-2-cyanoacetohydrazide (8), 2-amino-N\u27-benzylidene-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbohydrazide (9), 2-cyano-2-(2-(2-phenylhydrazono)cyclopentylidene)acetohydrazide (11), N\u27-(1-chloropropan-2-ylidene)-2-cyano-2-cyclopentylideneacetohydrazide (12), and the 2-cyclopentylidene-3-(3,5-disubstituted-1H-pyrazol-1-yl)-3-oxopropanenitriles 13a,b through its reaction with the respective reagents. The antitumor evaluation of the newly synthesized compounds against the three human tumor cells lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) showed that some of the described compounds exhibit higher inhibitory effects towards the three tumor cell lines than the reference compound doxorubicin

Design and Synthesis of Novel Antimicrobial Acyclic and Heterocyclic Dyes and Their Precursors for Dyeing and/or Textile Finishing Based on 2-N-Acylamino-4,5,6,7-tetrahydro-benzo[b]thiophene Systems

A series of novel polyfunctionalized acyclic and heterocyclic dye precursors and their respective azo (hydrazone) counterpart dyes and dye precursors based on conjugate enaminones and/or enaminonitrile moieties were synthesized. The dyes and their precursors are based on 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide, 2-ethoxycarbonyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide or 2-phenylcarbamoyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide systems as precursors. The latter compounds were used to synthesize polyfunctional thiophene-, thiazole-, pyrazole, pyridine-, pyrimidine-, oxazine-, as well as acyclic moieties. The dyes and dye precursors were characterized by elemental analysis and spectral methods. All dyes and their precursors were screened in vitro and evaluated for both their antibacterial and antifungal activities. MIC data of the novel dye systems and their respective precursors showed significant antimicrobial activity against most tested organisms. Some compounds exhibited comparable or even higher efficiency than selected standards. Dyes were applied at 5% depth for disperse dyeing of nylon, acetate and polyester fabrics. Their spectral characteristics and fastness properties were measured and evaluated