- Cinnamide derived pyrimidine-benzimidazole hybrids as tubulin inhibitors: Synthesis, in silico and cell growth inhibition studies
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An approach in modern medicinal chemistry to discover novel bioactive compounds is by mimicking diverse complementary pharmacophores. In extension of this strategy, a new class of piperazine-linked cinnamide derivatives of benzimidazole-pyrimidine hybrids have been designed and synthesized. Their in vitro cytotoxicity profiles were explored on selected human cancer cell lines. Specifically, structural comparison of target hybrids with tubulin-DAMA-colchicine and tubulin-nocodazole complexes has exposed a deep position of benzimidazole ring into the αT5 loop. All the synthesized compounds were demonstrated modest to interesting cytotoxicity against different cancer cell lines. The utmost cytotoxicity has shown with an amine linker of benzimidazole-pyrimidine series, with specificity toward A549 (lung cancer) cell line. The most potent compound in this series was 18i, which inhibited cancer cell growth at micromolar concentrations ranging 2.21–7.29 μM. Flow cytometry studies disclosed that 18i inhibited the cells in G2/M phase of cell cycle. The potent antitumor activity of 18i resulted from enhanced microtubule disruption at a similar level as nocodazole on β-tubulin antibody, explored using immunofluorescence staining. The most active compound 18i also inhibited tubulin polymerization with an IC50 of 5.72 ± 0.51 μM. In vitro biological analysis of 18i presented apoptosis induction on A549 cells with triggering of ROS generation and loss of mitochondrial membrane potential, resulting in DNA injury. In addition, 18i displayed impairment in cellular migration and inhibited the colony formation. Notably, the safety profile of most potent compound 18i was revealed by screening against normal human pulmonary epithelial cells (L132: IC50: 69.25 ± 5.95 μM). The detailed binding interactions of 18i with tubulin was investigated by employing molecular docking, superimposition and free energy analyses. Thus remarks made in this study established that pyrimidine-benzimidazole hybrids as a new class of tubulin polymerization inhibitors with significant anticancer activity.
- Sana, Sravani,Reddy, Velma Ganga,Srinivasa Reddy,Tokala, Ramya,Kumar, Rahul,Bhargava, Suresh K.,Shankaraiah, Nagula
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- Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis
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A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24, 2451-2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
- Patrick, Donald A.,Gillespie, J. Robert,McQueen, Joshua,Hulverson, Matthew A.,Ranade, Ranae M.,Creason, Sharon A.,Herbst, Zackary M.,Gelb, Michael H.,Buckner, Frederick S.,Tidwell, Richard R.
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supporting information
p. 957 - 971
(2017/02/19)
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- COMPOUNDS FOR TREATMENT OF TRYPANOSOMES AND NEUROLOGICAL PATHOGENS AND USES THEREOF
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The present invention relates to novel compounds that cross the blood-brain barrier and are effective inhibitors of neurological pathogens such as trypanosomes. The invention further relates to the use of these compounds for treating disorders related to trypanosomes and neurological pathogens.
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Paragraph 0192
(2017/09/24)
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- 6. 7 - dimethoxy - quinazoline - 4 - amine derivative, its preparation method and medical use
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The invention discloses a 6, 7-dimethoxy-quinazoline-4-amine derivative. The 6, 7-dimethoxy-quinazoline-4-amine derivative is characterized by having the following formula as shown in the specification, wherein in the formula, R1 represents hydrogen, meth
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Paragraph 0024
(2017/10/07)
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- Discovery of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives as novel VEGFR-2 kinase inhibitors
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Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. In this work, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives were designed and identified as potent inhibitors of VEGFR-2 (
- Shi, Lei,Wu, Ting-Ting,Wang, Zhi,Xue, Jia-Yu,Xu, Yun-Gen
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p. 698 - 707
(2014/08/18)
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- Combinatorial synthesis of benzimidazole-azo-phenol derivatives as antifungal agents
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A chemically diverse library of benzimidazole-azo-phenol derivatives was efficiently prepared and screened for their antifungal activities against five phytopathogenic fungi. Some compounds exhibited potent antifungal activities. As compared with a commercially available agricultural fungicide, hymexazol, especially compound V-5 showed the most promising broad-spectrum antifungal activities against five phytopathogenic fungi. The EC50 values of V-5 against F. graminearum, A. solani, V. mali, B. cinerea, and C. lunata were 0.09, 0.08, 0.06, 0.07, and 0.11 mol/mL, respectively.
- Ke, Yazhen,Zhi, Xiaoyan,Yu, Xiang,Ding, Guodong,Yang, Chun,Xu, Hui
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- Synthesis, p38 kinase inhibitory and anti-inflammatory activity of new substituted benzimidazole derivatives
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P38 mitogen activated protein kinases have been found to involve in the production and release of unwarranted levels of pro-inflammatory cytokines including TNFα and IL-1β in numerous inflammatory diseases. A new series of molecules, 5-substituted benzoylamino-2-substituted phenylbezimidazoles has been synthesized from 4-nitro-1, 2-diaminobenzene. The synthesized compounds were characterized by FTIR, 1HNMR and Mass. The final compounds were screened for in vitro p38 kinase inhibitory and in vivo anti-inflammatory activity. Three compounds from the series demonstrated nearly 50percent inhibition of p38 kinase in the in vitro screening method at 10 μM concentration and two molecules exhibited greater than 75percent inhibition of paw oedema volume during the first hour. The docking study of synthesized molecule revealed a new binding pose in ATP binding pocket.
- Kulkarni, Ravindra G.,Laufer, Stefan A.,Chandrashekhar,Garlapati, Achaiah
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- Novel anti-inflammatory and analgesic heterocyclic amidines that inhibit nitrogen oxide (NO) production
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Heterocyclic amidines with anti-inflammatory and analgesic activity that inhibit nitrogen oxide production, of formula (I): in which:G1 and G2 are hydrogen, halogen, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, and an amidino substituent of formula Q, provided that, for each compound of formula (I), only one of the two substituents G1 or G2 is an amidino substituent of formula Q: and in which the substituents W, Y and X are combined to form 9- or 10-membered bicyclic heteroaromatic derivatives containing up to 2 hetero atoms in the same ring; andZ is an aryl or heteroaryl group, a linear or branched C1-C6 alkyl or alkenyl chain, a C1-C4 alkyl-aryl group or a C1-C4 alkyl-heteroaryl group.
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Page/Page column 27
(2010/02/13)
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- Novel anti-inflammatory and analgesic heterocyclic amidines that inhibit nitrogen oxide (NO) production
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Heterocyclic amidines with anti-inflammatory and analgesic activity that inhibit nitrogen oxide production, of formula (I): in which: G1 and G2 are hydrogen, halogen, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, and an amidino substituent of formula Q, provided that, for each compound of formula (I), only one of the two substituents G1 or G2 is an amidino substituent of formula Q: and in which the substituents W, Y and X are combined to form 9- or 10-membered bicyclic heteroaromatic derivatives containing up to 2 hetero atoms in the same ring; and Z is an aryl or heteroaryl group, a linear or branched C1-C6 alkyl or alkenyl chain, a C1-C4 alkyl-aryl group or a C1-C4 alkyl-heteroaryl group.
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Page/Page column 19
(2010/02/13)
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- New Synthetic Applications of Aryllead Triacetates. N-Arylation of Azoles
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Treatment of a variety of azoles or their anions with p-tolyllead triacetate in the presence of copper(II) acetate afforded the corresponding N-aryl derivatives, normally in excellent yields.Room temperature arylation of an aminobenzimidazole derivative was chemoselectively directed to the amino group.
- Lopez-Alvarado, Pilar,Avendano, Carmen,Menendez, J. Carlos
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p. 5678 - 5682
(2007/10/03)
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- Imidazo(4,5-f)quinolines useful as immunomodulating agents
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The present invention involves compounds of the class of imidazo[4,5-f]quinolines and methods for enhancing the immune response system of mammals which comprises systemically administering to mammals having a depressed immune function an effective but non
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- 9-(P-phenylazoanilino)-7-methyl-1H-imidazo[4,5-f]quinolines
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A series of 9-(substituted amino)imidazo[4,5-f]quinolines are effective anthelmintic agents; particularly in respect to the tapeworm Hymenolepis nana.
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