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Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

ABSTRACT: The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3',4',5'-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure-activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice.

SUBMITTER: Romagnoli R

PROVIDER: S-EPMC3899843 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

Romagnoli Romeo R Baraldi Pier Giovanni PG Lopez-Cara Carlota C Preti Delia D Aghazadeh Tabrizi Mojgan M Balzarini Jan J Bassetto Marcella M Brancale Andrea A Fu Xian-Hua XH Gao Yang Y Li Jun J Zhang Su-Zhan SZ Hamel Ernest E Bortolozzi Roberta R Basso Giuseppe G Viola Giampietro G

Journal of medicinal chemistry 20131111 22

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3',4',5'-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure-activity relationship analysis established t ...[more]

PMID: 24164557

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Project description:BackgroundDespite significant progresses in antimicrobial therapy, infectious diseases caused by bacteria and fungi remain a major worldwide health problem because of the rapid development of resistance to existing antimicrobial drugs. Therefore, there is a constant need for new antimicrobial agents. There are a large number of heterocyclic derivatives containing nitrogen atoms that possess a broad spectrum of biological activities including pyridine and pyridazine, which are two of the most important heterocycles in medicinal chemistry.ResultsThe reaction of 3-oxo-2-arylhydrazonopropanals 2 with ethyl cyanoacetate and malononitrile 3a,b has led to the formation of 2-amino-5-arylazo-6-aryl substituted nicotinates 8a-k as sole isolable products when the aryl group in the arylazo moiety was substituted with an electron-withdrawing group like Cl, Br, NO2. The pyridazinones 10 were formed from the same reaction when the arylazo moiety was phenyl or phenyl substituted with an electron-donating group. The 2-aminoazonicotinates 8 were condensed with DMF-DMA to afford the amidines 13a,b, which then were cyclized to afford the targeted pyrido[2,3-d]pyrimidine derivatives 15a,b, respectively. The structures of all new substances prepared in this investigation were determined by using X-ray crystallographic analysis and spectroscopic methods. Most of the synthesized compounds were tested and evaluated as antimicrobial agents and the results indicated that many of the obtained compounds exhibited high antimicrobial activity comparable to ampicillin, which was used as the reference compound.ConclusionA general rule for the synthesis of 2-amino-5-arylazo-6-aryl substituted nicotinic acid and pyridazinone was established using 3-oxo-2-arylhydrazonopropanal as a precursor. Moreover, a novel route to pyrido[2,3-d]pyrimidine was achieved. Most of the synthesized compounds were found to exhibit strong inhibitory effects on the growth of Gram-positive bacteria especially Bacillus subtilis. Compounds 1a, 8a-h, 10a-c, 15b and 16 showed a broad spectrum of antimicrobial activity against B. subtilis.

Dataset Information

Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

Publications

Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

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