- Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies
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Abstract: The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC50 = 3.61?μM), followed by 21 which displayed IC50 value of 3.93?μM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand–protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles. Graphic abstract: [Figure not available: see fulltext.]
- Turky, Abdallah,Bayoumi, Ashraf H.,Sherbiny, Farag F.,El-Adl, Khaled,Abulkhair, Hamada S.
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p. 403 - 420
(2020/08/25)
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- Synthesis, in silico Study and Antileishmanial Evaluation of New Selenides Derived from 7-Chloro-quinoline and N-Phenylacetamides
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This study describes a virtual screening performed for two series of selenides (28 compounds), derived from N-phenylacetamides chlorides and 7-chloro-quinoline, to determine their potential for leishmanicidal activity against Leishmania amazonensis and Leishmania donovani. Seven compounds were predicted as potential leishmanicides; therefore, they were synthesized from elemental selenium, as a precursor for the production of NaHSe, and subsequent reactions with 4,7-dichloro-quinoline and N-phenylacetamides chlorides were performed. The compounds were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR), and sent for in vitro cytotoxicity tests against L. amazonensis and were found to be active and selective, and two compounds presented half-maximal inhibitory concentrations (IC50) of 5.67 and 10.81 μg mL-1. They also presented good interaction energies in the docking study, suggesting that may exert their effects by inhibiting the N-myristoyltransferase and O-acetylserine sulfhydrylase enzymes in parasites.
- Huang, Min-Fu N.,Luis, José A.S.,da Silva, Alison P.,Rocha, Juliana C.,Lima, Tatjana K.S.,Scotti, Marcus T.,Scotti, Luciana,de Oliveira, Rafael F.,Souza, Helivaldo D.S.,de Athayde-Filho, Petr?nio F.,Barbosa-Filho, José M.
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p. 712 - 721
(2021/03/17)
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- Synthesis method of 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone
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The invention provides a synthesis method of 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone. The synthesis method comprises the following steps: 1) taking p-alkoxyaniline as a raw material to react with 3-chloro-propionyl chloride, so as to prepare N-(4-alkoxyphenyl)-3-chloropropene amide; 2) dissolving the N-(4-alkoxyphenyl)-3-chloropropene amide obtained by step 2) into an organic solvent and adding acatalyst palladium chloride; raising the temperature to 100 to 110 DEG C under the pressure of 3 to 5kg, and carrying out heat preservation and reaction for 3 to 4h; after cooling to room temperature, filtering; spinning and drying filtrate to remove the organic solvent, so as to obtain a 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone crude product; 3) recrystallizing the 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone crude product obtained by step 3), de-coloring and filtering to obtain an off-white color solid 6-hydroxyl-3,4-dihydro-2(1H)-quinolinone. The synthesis method has the advantages of simplicity in operation, high yield and lower cost.
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Paragraph 0032
(2018/09/08)
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- Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors
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Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the prese
- Zhu, Kongkai,Song, Jia-Li,Tao, Hong-Rui,Cheng, Zhi-Qiang,Jiang, Cheng-Shi,Zhang, Hua
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supporting information
p. 3693 - 3699
(2018/10/24)
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- Preparation method of cilostazol
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The invention discloses a preparation method of cilostazol and belongs to the field of medicines. The preparation method comprises the following steps: firstly, reacting 4-methoxyaniline with 3-chloropropionyl chloride in the presence of a solvent or no solvent; after a TLC (thin layer chromatography) detecting reaction is finished, adding aluminum trichloride into a system, and carrying out temperature raising reaction for 1 to 16 hours to obtain 6-hydroxy-3,4-dihydroquinoline-2-keto; secondly, in the presence of alkali, carrying out heating reaction on the 6-hydroxy-3,4-dihydroquinoline-2-keto obtained in the first step and 5-(4-chlorobutyl)-1-cyclohexanyl tetrazole in normal propyl alcohol to obtain the cilostazol. The high-purity cilostazol can be obtained by adopting the method disclosed by the invention; the preparation method has the advantages of few steps of the whole synthetic route, high yield, low cost, less wastewater and suitability for industrial production.
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Paragraph 0039-0040; 0043-0044; 0046-0047; 0049-0050; 0052
(2018/01/03)
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- Platinum(II) complexes with amide-functionalized NHC ligands
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We present the synthesis of neutral, amide-functionalized N-heterocyclic carbene (NHC) platinum(II) complexes with dianionic -N-CNHC-C NHC-N- (NCCN) tetradentate ligands. The imidazolium- and bisimidazolium bromide NHC lig
- Unger, Yvonne,Strassner, Thomas
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experimental part
p. 203 - 208
(2012/08/07)
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- Synthesis of novel 3,4-dihydroquinolin-2(1H)-one guanidines as potential antihypertensive agents
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Hydroxy-3,4-dihydroquinolin-2(1H)-ones (4a-c) were synthesized by intramolecular Friedel Craft alkylation of N-(methoxyphenyl)-3- chloropropionamides (3a-c), obtained by acylation of anisidine with chloropropionyl chloride. The hydroxy-3,4-dihydro quinolin-2(1H)- ones (4a-c) were treated with various dibromo alkanes under phase transfer catalyst conditions at room temperature to give bromoalkyloxy- 3,4-dihydroquinolin-2(1H)- ones (5a-l) which on further reaction with guanidine hydrochloride in dimethyl formamide afforded N-{4- [(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy]alkyl} guanidines (6a-l). These compounds were synthesized as potential antihypertensive agents.
- Pai,Samel
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experimental part
p. 1655 - 1660
(2012/01/06)
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- Synthesis and biological screening of novel derivatives of 3-(N-substituted carboxamidoethylthio)-(4H)-1,2,4-triazoles
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3-Mercapto-(4H)-1,2,4-triazole has been synthesized from 1-formylthiosemicarbazide. Different N-substituted β-chloropropionamides have been prepared by reacting substituted amines with β- chloropropionylchloride. Different Nsubstituted β-chloropropionamides have been condensed with 3-mercapto-(4H)-1,2,4-triazole in basic medium to obtain various 3-(N-substituted carboxamidoethylthio)-(4H)-1,2,4-triazoles. The structure of the synthesized compounds are confirmed by IR, 1H NMR spectra and elemental analysis. All the compounds have been screened for their analgesic, anti-inflammatory and anxiolytic activity.
- Manikrao, Anil M.,Fursule, Ravindra A.,Rajesh,Kunjwani, Harish K.,Sabale, Prafulla M.
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experimental part
p. 1642 - 1647
(2011/03/17)
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- Processes for preparing 6-hydroxy-3,4-dihydroquinolinone, cilostazol and N-(4-methoxyphenyl)-3-chloropropionamide
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A process for preparing 6-hydroxy-3,4-dihydroquinolinone by intramolecular Friedel-Crafts alkylation of N-(4-methoxyphenyl)-3-chloropropionamide in which an equivalent of N-(4-methoxyphenyl)-3-chloropropionamide is contacted with a Lewis acid in DMSO or a high boiling amide or amine at an elevated temperature of from about 150° C. to about 220° C. is provided. The process produces 6-HQ in high yield and a high state of purity such that it may be used in subsequent reactions toward the preparation of cilostazol without intermediate purification. A process for preparing cilostazol from 6-hydroxy-3,4-dihydroquinolinone prepared by the process and improved processes for preparing N-(4-methoxyphenyl)-3-chloropropionamide are also provided.
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- Aluminium chloride-catalyzed intermolecular vs intramolecular friedel-crafts reaction of acrylanilides and 3-chloropropanamides
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3-Phenylpropionanilide (4a) is obtained in a yield of 89% from acrylanilide by the treatment with AlCl3/ benzene, compared with a yield of 39% by the 1,4-conjugate addition of phenyllithium. The formation of 4a indicated that an intermolecular Friedel-Crafts reaction occurred, rather than the relatively more facile intramolecular ring cyclization, and provided a more efficient route than a conjugate addition of phenyllithium for the preparation of 3-phenylpropionanilide and its derivatives. Although the methoxy group is an activator of the nucleophilic substitution, introduction of a methoxy substituent at N-phenyl did not increase the competitive capability of the intramolecular cyclization because of AlCl3-catalyzed demethylation to form the ArOAlCl2 complex which decreased the availability of the π-electron in the N-phenyl aromatic system.
- Chen, I.-Li,Wang, Tai-Chi,Chen, Yeh-Long,Tzeng, Cherng-Chyi
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p. 155 - 162
(2007/10/03)
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