Design, synthesis and anticonvulsant evaluation of novel N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothio amides

Tripathi, Laxmi; Kumar, Praveen; Singh, Ranjit; Stables, James P.

doi:10.1016/j.ejmech.2011.10.038

Cited by 32 publications

(27 citation statements)

References 18 publications

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“…Calculated predicted percent oral absorption by using following formula Predicted percent oral absorption = 109 -(TPSA × 0.345) × 100. All derivatives showed acceptable Lipinski parameters and oral absorption within 61% 17,18,19 and 75% as shown table no. 3 .…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

Exploration of Anticancer Potential of Spiropyranopyrazole Derivatives as CDK7 Inhibitors

Bhatia

Kumbhar

Kawade

et al. 2016

Journal of Pharmaceutical Research

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: Purpose :Findings :Social Implications :Original : Key words :The Spiropyranopyrazole derivatives are used as cytotoxic agents and nitrogen containing heterocyclic analogs targeting CDK7 inhibition shows better cytotoxic activity. Methodology: A new series of compounds were synthesized using various substituted isatin derivatives and then characterized and analyzed for biological activity by in-silico and using MTT assay targeting CDK7. All the synthesized compounds were analyzed for their biological activity for this purpose breast cancer cell lines (MCF7) were used and analyzed by MTT assay. Docking studies into ATP binding site of CDK7 were performed to predict their binding affinity scores and possible interactions with receptor to evaluate bioactivity in-silico using VLife MDS 4.3.A novel series of Spiropyranopyrazole derivatives were successfully synthesized via Multicomponent reaction (MCR). From experimental data indicated that compounds 2c and 3c showed most promising results as their inhibitory activity with 23.20% and 26.50% respectively at 10µM and these were selected for further preclinical studies.If the present findings of spiropyranopyrazole derivatives passes preclinical studies and we develop drug like candidate then it is a massive achievement in anticancer therapy that could save many lives.Successfully develop a novel series of spiropyranopyrazole having CDK7 inhibitor activity. This could be helpful for development of a drug like candidate having significant cytotoxic activity.

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Section: Pharmacokinetic Studymentioning

confidence: 99%

Exploration of Anticancer Potential of Spiropyranopyrazole Derivatives as CDK7 Inhibitors

Bhatia

Kumbhar

Kawade

et al. 2016

Journal of Pharmaceutical Research

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“…For select compounds, additional characterization includes 13 C NMR (2, 3, 4, 13x, 14, 15, 16, 17, 19a, 28), FTIR (2−5, 13x, 28), and melting point (2, 13x). NMR spectra are provided for select compounds.…”

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confidence: 99%

Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

Jung

Chamberlain

et al. 2014

ACS Med. Chem. Lett.

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EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure− activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3−5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC 50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis. KEYWORDS: Photoaffinity labeling, semicarbazone, aryl azide, anthrax lethal toxin, endosomal trafficking A common mechanism by which viruses and bacterial toxins enter host cells involves trafficking from an early to a late endosome followed by release into the cytoplasm as triggered by endosomal acidification. 1−3 Inhibition of this process represents a host-targeted strategy for the development of broad-spectrum antiviral and antibacterial drugs. Recently, EGA, N 1 -(4-bromobenzylidene)-N 4 -(2,6-dimethylphenyl)-semicarbazone, 1, was identified from a high-throughput phenotypic screen to protect cells from anthrax lethal toxin (LT). 4 Further investigations showed that 1 protected cells from multiple viruses and bacterial toxins that rely on pHdependent endosomal trafficking to enter cells. Although the details of the biochemical mechanism have been studied, the cellular target(s) remain unknown. We have conducted a structure−activity relationship (SAR) study with the goal of improving the potency of 1 and developing a strategy for photoaffinity labeling and identification of the involved proteins.A series of derivatives of 1 were synthesized and tested, revealing precise requirements for activity in a tight and relatively flat structure−activity landscape. The 2,6-dimethyl substitution in the N 4 -ring as well as an unaltered semicarbazone core were shown to be optimal for activity while certain modifications to the N 1 -phenyl ring were tolerated. From the SAR, a compound more potent than the original hit was generated, namely the N 1 -2-fluoro-4-bromophenyl analogue (IC 50 = 0.4 μM), 2. In addition, three photoaffinity probes, 3−5, two of which possess low micromolar activity, were designed and synthesized. Our key finding is that the expected photochemistry of the phenyl azide moiety is a more important factor than the IC 50 of the photoprobe in achieving successful photolabeling. While 3 was the most potent inhibitor of intoxication by LT in the standard assay, it did not provide protection to the cells upon UV photolysis. Conversely 5, which possesses two fluorine atoms ortho to the azido function, was a poor inhibitor in the stand...

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“…A literature survey revealed that benzothiazole analogs are associated with diverse pharmacological effects [11][12][13][14], including anticonvulsant activity [15,16]. For this reason, and in continuation to our efforts directed toward the synthesis of new heterocyclic compounds with anticonvulsant biological activities, in this study, we combined both biological components (3-mercapto-1,2,4-triazole and benzothiazole) with an amide, which has anticonvulsant bioactivities in some AEDs (such as carbamazepine and riluzole, also see references [17,18]), to obtain a series of 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl)acetamide. To compare the compound activities with those of other azoles, the mercapto-triazole in compound 5 was replaced with other heterocycles such as imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole, to obtain compounds 6, 7, 8, and 9 ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Molecules 2016, 21, 164 2 of 13 which has anticonvulsant bioactivities in some AEDs (such as carbamazepine and riluzole, also see references [17,18]), to obtain a series of 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl) acetamide. To compare the compound activities with those of other azoles, the mercapto-triazole in compound 5 was replaced with other heterocycles such as imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole, to obtain compounds 6, 7, 8, and 9 ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Potential Anticonvulsant Agents

et al. 2016

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New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((3-fluorobenzyl) oxy)benzo[d]thiazol-2-yl)acetamide (5i) and 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((4-fluorobenzyl)oxy) benzo[d] thiazol-2-yl)acetmide (5j) were the most potent, with an ED 50 value of 50.8 mg/kg and 54.8 mg/kg in the MES test and 76.0 mg/kg and 52.8 mg/kg in the scPTZ seizures test, respectively. They also showed lower neurotoxicity and, therefore a higher protective index. In particular, compound 5j showed high protective index (PI) values of 8.96 in the MES test and 9.30 in the scPTZ test, which were better than those of the standard drugs used as positive controls in this study.

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Design, synthesis and anticonvulsant evaluation of novel N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothio amides

Cited by 32 publications

References 18 publications

Exploration of Anticancer Potential of Spiropyranopyrazole Derivatives as CDK7 Inhibitors

Exploration of Anticancer Potential of Spiropyranopyrazole Derivatives as CDK7 Inhibitors

Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Potential Anticonvulsant Agents

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