Synthesis and structure elucidation of some novel thiophene and benzothiophene derivatives as cytotoxic agents

Mohareb, Rafat M.; Abdallah, Amira E. M.; Helal, M. A.; Shaloof, Somiya M. H.

doi:10.1515/acph-2016-0005

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…15) In the present work we were concerned through exploring the reactivity of the amino group present in the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene 16) towards different chemical reagents to afford a vast number of heterocyclic compounds involving tetrahydrobenzo[b]-thiophene moiety and evaluating their cytotoxicity.…”

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confidence: 99%

“…14) In addition, we were involved through the reaction of ethyl acetoacetate with elemental sulphur and either malononitrile or ethyl cyanoacetate gave thiophene derivatives. 15) In the present work we were concerned through exploring the reactivity of the amino group present in the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene 16) towards different chemical reagents to afford a vast number of heterocyclic compounds involving tetrahydrobenzo[b]-thiophene moiety and evaluating their cytotoxicity.…”

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Synthesis of Novel Heterocyclic Compounds Incorporate 4,5,6,7-Tetrahydrobenzo[<i>b</i>]thiophene Together with Their Cytotoxic Evaluations

Abdallah

Mohareb

Khalil

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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The 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene was the key starting compound used to synthesize new thiazole, pyrimidine, pyran, pyridine and thiazine derivatives. The cytotoxicity of the synthesized compounds was studied towards the three cancer cell lines namely MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (central nervous system (CNS) cancer) in addition to the normal cell line (WI-38) using doxorubicin as the reference drug. The study showed that compounds 5, 9a, 15b, 17c, 18 and 21b were the most potent compounds. anti-leishmanial agents, 11) antioxidant activity, 12) anti-arrhythmic, serotonin antagonist and anti-anxiety activities. Key words 13)Recently we were involved through the synthesis of polyfunctional heterocyclic compounds, where the 2-cyanomethylbenzo[c] imidazole was used as the key starting compound.14) In addition, we were involved through the reaction of ethyl acetoacetate with elemental sulphur and either malononitrile or ethyl cyanoacetate gave thiophene derivatives. 15) In the present work we were concerned through exploring the reactivity of the amino group present in the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene 16) towards different chemical reagents to afford a vast number of heterocyclic compounds involving tetrahydrobenzo[b]-thiophene moiety and evaluating their cytotoxicity. Results and DiscussionChemistry The reaction of the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene with triethyl orthoformate in acetic acid gave the ethyl N- (3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) formimidate 1. The analytical and spectral data of compound 1 were the tools of its structural elucidation. Compound 1 reacted with aniline to give the N-phenyl formamidine derivative 2. The elemental and spectral data of compound 2 were consistent with its proposed structure. Thus, 1 H-NMR spectrum of compound 2 showed, beside the expected signals, a singlet at 6.95 ppm δ for CH moiety, a muliplet at δ 7.27-7.90 ppm for phenyl ring and a singlet at δ 8.36 ppm for NH group. On the other hand, the reaction of compound 1 with malononitrile gave the imino-methyl malononitrile derivative 3. The analytical and spectral data of compound 3 were in agreement with its structure (see Experimental section). The reaction of compound 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene with phenylisothiocyanate and chloroacetone gave the thiazole derivative 5. Formation of the latter product took place through the intermediate formation of 4 followed by water elimination (Chart 1).Next we studied the possibility of compound 2-amino-3-cyano-4, 5,6,7-tetrahydrobenzo[b] thiophene to form thiourea derivative. Thus, compound 2-amino-3-cyano-4, 5,6,7-tetrahydrobenzo[b] thiophene reacted with phenyl

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confidence: 99%

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confidence: 99%

Synthesis of Novel Heterocyclic Compounds Incorporate 4,5,6,7-Tetrahydrobenzo[<i>b</i>]thiophene Together with Their Cytotoxic Evaluations

Abdallah

Mohareb

Khalil

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…A large number of these derivatives have reached clinical trials, and many have been marketed [3,4]. This system has also attracted great attention due to its versatile synthetic approaches and the reported broad biological activities [5][6][7][8] that range from antihypertensive through alpha-1 adrenergic receptor antagonism [9], antiplatelet aggregation [10], antidepressant activity [11], treatment of erectile dysfunction, phosphodiesterase-5 inhibition [12], anti-inflammatory through COX-II inhibition [13], antimicrobial activity [14,15], and many other pledging activities [8], Noteworthy is the antiproliferative activity in which thienopyrimidine derivatives display potent activity with several mechanisms of action such as PI3K pathway inhibition [8,16,17], focal adhesion kinase (FAK) inhibition [18], kinases inhibitory activity against Tie-2 [19], cell cycle arrest and apoptosis induction [20][21][22]. Last but not least, they have promising anticancer activity by inhibiting the pathways under investigation,VEGFR-2 [23,24] and AKT-1 [25], that end in cancer cell proliferation, growth, and survival inhibition.…”

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confidence: 99%

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

et al. 2022

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Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 μM) and 4c (IC50 = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 μM, respectively, while 3b showed IC50 = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.

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“…Mohareb et al [30] developed a convenient synthetic approach for novel thiophene and benzothiophene derivatives (Scheme 14). The in vitro cytotoxicity was screened against three tumor cell lines–MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer) and a normal fibroblast human cell line (WI-38) compared to the anti-proliferative effects of the reference control doxorubicin.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic importance of synthetic thiophene

Shah

Verma

2018

Chemistry Central Journal

178

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Thiophene and its substituted derivatives are very important class of heterocyclic compounds which shows interesting applications in the field of medicinal chemistry. It has made an indispensable anchor for medicinal chemists to produce combinatorial library and carry out exhaustive efforts in the search of lead molecules. It has been reported to possess a wide range of therapeutic properties with diverse applications in medicinal chemistry and material science, attracting great interest in industry as well as academia. It has been proven to be effectual drugs in present respective disease scenario. They are remarkably effective compounds both with respect to their biological and physiological functions such as anti-inflammatory, anti-psychotic, anti-arrhythmic, anti-anxiety, anti-fungal, antioxidant, estrogen receptor modulating, anti-mitotic, anti-microbial, kinases inhibiting and anti-cancer. Thus the synthesis and characterization of novel thiophene moieties with wider therapeutic activity is a topic of interest for the medicinal chemist to synthesize and investigate new structural prototypes with more effective pharmacological activity. However, several commercially available drugs such as Tipepidine, Tiquizium Bromides, Timepidium Bromide, Dorzolamide, Tioconazole, Citizolam, Sertaconazole Nitrate and Benocyclidine also contain thiophene nucleus. Therefore, it seems to be a requirement to collect recent information in order to understand the current status of the thiophene nucleus in medicinal chemistry research.

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Synthesis and structure elucidation of some novel thiophene and benzothiophene derivatives as cytotoxic agents

Cited by 16 publications

References 31 publications

Synthesis of Novel Heterocyclic Compounds Incorporate 4,5,6,7-Tetrahydrobenzo[<i>b</i>]thiophene Together with Their Cytotoxic Evaluations

Synthesis of Novel Heterocyclic Compounds Incorporate 4,5,6,7-Tetrahydrobenzo[<i>b</i>]thiophene Together with Their Cytotoxic Evaluations

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

Therapeutic importance of synthetic thiophene

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