- Discovery of Isatin-Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase
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Using ligand-based design strategy, a set of isatin-3-carbohydrazones was designed, synthesized and evaluated for dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition properties. Compound 5-chloro-N′-(5-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 b) emerged as a potent MAGL inhibitor with nanomolar activity (IC50=3.33 nM), while compound 5-chloro-N′-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 j) was the most potent selective FAAH inhibitor (IC50=37 nM). Compound 5-chloro-N′-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 c) showed dual FAAH-MAGL inhibitory activity with an IC50 of 31 and 29 nM respectively. Enzyme kinetics studies revealed that the isatin-based carbohydrazones are reversible inhibitors for both FAAH and MAGL. Further, blood-brain permeability assay confirmed that the lead compounds (13 b, 13 c, 13 g, 13 m and 13 q) are suitable as CNS candidates. Molecular dynamics simulation studies revealed the putative binding modes and key interactions of lead inhibitors within the enzyme active sites. The lead dual FAAH-MAGL inhibitor 13 c showed significant antioxidant activity and neuroprotection in the cell-based cytotoxicity assay. In summary, the study yielded three potent FAAH/MAGL inhibitor compounds (13 b, 13 c and 13 j) with acceptable pharmacokinetic profile and thus can be considered as promising candidates for treating neurological and mood disorders.
- Jaiswal, Shivani,Ayyannan, Senthil Raja
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- Design, modification of phyllanthone derivatives as anti-diabetic and cytotoxic agents
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Twelve benzylidene derivatives, one Baeyer-Villiger oxidative, six imine derivatives were successfully designed and synthesised from phyllanthone. In the search for potential new anti-diabetic agents, phyllanthone along with its benzylidene and oxidation analogues were evaluated for enzyme inhibition against α-glucosidase. In the benzylidene series, most analogues displayed stronger activity than the mother compound. Compound 1c revealed the strongest activity, outperforming the acarbose positive control with an IC50 value of 19.59 μM. Phyllanthone and its derivatives were then tested for cytotoxic activity against the K562 cell line. The imine analogues displayed the most powerful cytotoxic activity with 3cand 3d having IC50 values of 57.55 and 68.02 μM, respectively.
- Nguyen, Ngoc-Hong,Vo, Van-Giau,Phan, Hoang-Vinh-Truong,Ngo, Thanh-The,Sichaem, Jirapast,Nguyen, Thi-Phuong,Nguyen, Huu-Hung,Pham, Duc-Dung,Nguyen, Tien-Cong,Nguyen, Van-Kieu,Duong, Thuc-Huy
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p. 371 - 378
(2020/07/13)
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- Synthesis, α-glucosidase inhibition, and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents
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A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2–13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2–13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.
- Alam, Mahboob,Chavasiri, Warinthorn,Duong, Thuc-Huy,Huynh, Ngoc-Vinh,Nguyen, Huu-Hung,Nguyen, Thi-Phuong,Nguyen, Tien-Cong,Paramita Devi, Asshaima,Phan, Hoang-Vinh-Truong,Sichaem, Jirapast,Tran, Hoai-Duc,Tran, Nguyen-Minh-An
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- Evaluation of novel N′-(3-hydroxybenzoyl)-2-oxo-2H-chromene-3-carbohydrazide derivatives as potential HIV-1 integrase inhibitors
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In an attempt to identify potential new agents that are active against HIV-1 IN, a series of novel coumarin-3-carbohydrazide derivatives were designed and synthesised. The toxicity profiles of these compounds showed that they were non-toxic to human cells and they exhibited promising anti-HIV-1 IN activities with IC50 values in nM range. Also, an accompanying molecular modeling study showed that the compounds bind to the active pocket of the enzyme.
- Jesumoroti, Omobolanle J.,Faridoon,Mnkandhla, Dumisani,Isaacs, Michelle,Hoppe, Heinrich C.,Klein, Rosalyn
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- Synthesis, biological evaluation, and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents
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A series of pyrazolyl-acylhydrazone derivatives (1e-20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC50 = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.
- Xing, Man,Zhao, Ting-Ting,Ren, Yu-Jia,Peng, Na-Na,Yang, Xian-Hui,Li, Xi,Zhang, Hui,Liu, Gao-Qi,Zhang, Li-Rong,Zhu, Hai-Liang
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p. 3274 - 3286
(2014/06/24)
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- ANTI-BACTERIAL PYRUVATE KINASE MODULATOR COMPOUNDS, COMPOSITIONS, USES, AND METHODS
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Compounds having a structure of Formulas A-C are provided. Uses of such compounds as an antibiotic, including both gram-negative and gram-positive micro-organisms, as well as methods of treatment and uses involving such compounds are provided.
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Page/Page column 71
(2012/05/05)
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- Optimization and structure-activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents
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A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected 'hub proteins' in MRSA. PK has been shown to b
- Kumar, Nag S.,Amandoron, Emily A.,Cherkasov, Artem,Brett Finlay,Gong, Huansheng,Jackson, Linda,Kaur, Sukhbir,Lian, Tian,Moreau, Anne,Labrière, Christophe,Reiner, Neil E.,See, Raymond H.,Strynadka, Natalie C.,Thorson, Lisa,Wong, Edwin W.Y.,Worrall, Liam,Zoraghi, Roya,Young, Robert N.
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p. 7069 - 7082
(2013/01/15)
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- ANTIALLERGIC
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A medicament for the preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each ofX and E has the same meaning as that defined above.
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Page/Page column 166
(2010/02/11)
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- IMMUNITY-RELATED PROTEIN KINASE INHIBITORS
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[From equivalent EP1510210A1] A medicament having an inhibitory activity against IKK-Aβ and/or MEKK-1 or other protein kinases structurally similar thereto, which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above.
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Page/Page column 163
(2010/02/10)
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- INHIBITORS AGAINST THE ACTIVATION OF AP-1 AND NFAT
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A medicament inhibiting the activation of AP-1 which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above.
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Page/Page column 161
(2008/06/13)
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