- Synthesis, structure analysis, DFT calculations and energy frameworks of new coumarin appended oxadiazoles, to regress ascites malignancy by targeting VEGF mediated angiogenesis
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Ascites malignancy is a frequent cause of morbidity and presents significant management problems which occur in many cancers. Angiogenesis plays a major role in the prognosis of ascites tumor through Vascular Endothelial Growth Factor (VEGF). Inhibition o
- Banumathi,Jyothi, Mahima,Khamees, Hussien Ahmed,Khanum, Shaukath Ara,Prabhakar, B. T.,Sherapura, Ankith,Zabiulla
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- Design, docking, synthesis, and characterization of novel N'(2-phenoxyacetyl) nicotinohydrazide and N'(2-phenoxyacetyl)isonicotinohydrazide derivatives as anti-inflammatory and analgesic agents
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Inflammation is the complex biological response of vascular tissues, which is partly determined by prostaglandins (PLA2). The cyclooxygenase (COX) enzyme exists in two isoforms: COX-1 and COX-2 and by the action of this, the PGs are produced. Besides, nonsteroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents useful in the treatment of inflammation. Encouraged by this, the new derivatives of N'(2-phenoxyacetyl)nicotinohydrazide 9(a-e) and N'(2-phenoxyacetyl)isonicotinohydrazide 10(a-e) were designed, synthesized, characterized, and identified as remarkable anti-inflammatory and analgesic agents. These compounds were prepared in a series of steps starting with different phenol derivatives. Among the series, compound (10e) showed the highest IC50 value for COX-1 inhibition, whereas compounds (9e) and (10e) exhibited the highest COX-2SI. Further, molecular Docking Studies have been performed for the potent compound to check the three-dimensional geometrical view of the ligand binding to the targeted enzymes.
- Al-Ostoot, Fares Hezam,Khanum, Shaukath Ara,M, Pallavi H,Vivek, Hamse Kameshwar
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- Design, synthesis and biological evaluation of oxime lacking Psammaplin inspired chemical libraries as anti-cancer agents
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In this study, we attempted the chemical simplification of Psammaplin (PsA), while retaining its activity in vitro. Inspired by the previous Structure Activity Relationship (SAR) studies on various PsA analogues and relying on the fact that oxime is metabolically unstable, we initially designed and synthesized a diverse library of PsA analogues and evaluated for cytotoxic activity. Among 32 compounds of Psammaplin analogues synthesized, the compound 10b was almost equally active as parent Psammaplin in vitro.
- Ali, Kasim,Chaturvedi, Priyank,Datta, Dipak,Kumar M, Srinivas Lavanya,Meena, Sanjeev,Panda, Gautam
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- Discovery, synthesis and biological characterization of a series of: N -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1 H -pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators
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The present study describes the discovery and characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds. This journal is
- Alnouti, Yazen,Aretz, Christopher D.,Chhonker, Yashpal S.,Dhuria, Nikilesh V.,Du, Yu,Gautam, Nagsen,Hopkins, Corey R.,Kumar, Sushil,Lesiak, Lauren,Sharma, Swagat,Weaver, C. David
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supporting information
p. 1366 - 1373
(2021/09/28)
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- Synthesis, evaluation and in silico studies of novel BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold
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Abstract: The BRD4 protein is associated with various diseases, which has been an attractive target for the treatment of cancer and inflammation. This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold. The SARs focused on exploration of the 2′ or 3′ position to afford novel inhibitors that may avoid potential metabolically unstable site. The most potent inhibitor 13f exhibited high binding affinity to BRD4(1) with a ΔTm value of 7.8 °C as evaluated in thermal shift assay (TSA). The potent activity was also demonstrated by a peptide competition assay with an IC50 value of 0.21?μM. The docking studies revealed the binding mode of the compounds with the active site of BRD4(1). In addition, in silico predictions indicated that these compounds possessed good drug-likeness and pharmacokinetic profile. Graphic abstract: This paper is a follow-up to our previous studies, in which we report the structure-based design,synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazolscaffold.[Figure not available: see fulltext.].
- Zhang, Maofeng,Liu, Zhuyun,Wang, Lizhong,Li, Yan,Ma, Yonggang
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- Molecular docking and synthesis of caffeic acid analogous and its anti-inflammatory, analgesic and ulcerogenic studies
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A series of caffeic acid (CA) derivatives 7a-j were synthesized via etherification and coupling action and their chemical structures were elucidated spectroscopically. Motivated by the various biological activities displayed by CA derivatives such as anti-inflammatory, antiviral, anticancer and antioxidant and also based on its extensively consumption in the human diet. In the present work, the newly synthesized compounds 7a-j were evaluated for anti-inflammatory and analgesic action and most of them exerted comparable activity to the reference compound celecoxib. Further, ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drug. Among the title series 7a-j, compounds 7f and 7g with electron withdrawing bromo and chloro group respectively, at the para position of the phenoxy ring was showed good activity compared to all other compounds. Interestingly, the COX-I/COX-II activity ratio of potent compounds 7f and7g showed an almost equal inhibitory effect on both isoenzymes. Further, molecular docking studies have been performed for the potent compounds which showed statistically significant result.
- Al-Ostoot, Fares Hezam,Ara Khanum, Shaukath,Grisha, S.,Mohammed, Yasser Hussein Eissa,Vivek, H. K.,Zabiulla
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- Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia
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Background: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. Methods: A new series of DPA (7a–t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. Results: Initial in vitro anti-proliferative screening of Compounds DPA (7a–t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3?μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. Conclusions: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity. Graphic abstract: [Figure not available: see fulltext.]
- Al-Ostoot, Fares Hezam,Sherapura, Ankith,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Muhimeed, Tahani I.,Khanum, Shaukath Ara,Prabhakar
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p. 1344 - 1360
(2021/06/14)
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- Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression
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Background: Hypoxic microenvironment is a common feature of solid tumors, which leads to the promotion of cancer. The transcription factor, HIF-1α, expressed under hypoxic conditions stimulates tumor angiogenesis, favoring HIF-1α as a promising anticancer agent. On the other hand, synthetic Indolephenoxyacetamide derivatives are known for their pharmacological potentiality. With this background here, we have synthesized, characterized, and validated the new IPA (8a–n) analogs for anti-tumor activity. Methods: The new series of IPA (8a–n) were synthesized through a multi-step reaction sequence and characterized based on the different spectroscopic analysis FT-IR, 1H, 13C NMR, mass spectra, and elemental analyses. Cell-based screening of IPA (8a–n) was assessed by MTT assay. Anti-angiogenic efficacy of IPA (8k) validated through CAM, Rat corneal, tube formation and migration assay. The underlying molecular mechanism is validated through zymogram and IB studies. The in vivo anti-tumor activity was measured in the DLA solid tumor model. Results: Screening for anti-proliferative studies inferred, IPA (8k) is a lead molecule with an IC50 value of ?5?μM. Anti-angiogenic assays revealed the angiopreventive activity through inhibition of HIF-1α and modulation downstream regulatory genes, VEGF, MMPs, and P53. The results are confirmative in an in vivo solid tumor model. Conclusion: The IPA (8k) is a potent anti-proliferative molecule with anti-angiogenic activity and specifically targets HIF1α, thereby modulates its downstream regulatory genes both in vitro and in vivo. The study provides scope for new target-specific drug development against HIF-1α for the treatment of solid tumors. Graphic abstract: [Figure not available: see fulltext.].
- Al-Ostoot, Fares Hezam,Sherapura, Ankith,V, Vigneshwaran,Basappa, Giridhara,H.K, Vivek,B.T, Prabhakar,Khanum, Shaukath Ara
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p. 1328 - 1343
(2021/05/03)
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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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- Novel sulfonyl chloride derivative as well as preparation method and application thereof
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The invention provides a novel sulfonyl chloride derivative as well as a preparation method and an application thereof. The structural formula of the sulfonyl chloride derivative is as shown in a formula I, which is described in the specification. The pre
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Paragraph 0036-0041
(2019/12/02)
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- 2-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety
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Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.
- Dow, Robert L.,Ammirati, Mark,Bagley, Scott W.,Bhattacharya, Samit K.,Buckbinder, Leonard,Cortes, Christian,El-Kattan, Ayman F.,Ford, Kristen,Freeman, Gary B.,Guimar?es, Cristiano R. W.,Liu, Shenping,Niosi, Mark,Skoura, Athanasia,Tess, David
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supporting information
p. 3114 - 3125
(2018/04/23)
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- The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections
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Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ± 0.003 μM) and intact cell (IC50 = 0.89 ± 0.05 μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.
- Ni, Wei-Wei,Liu, Qi,Ren, Shen-Zhen,Li, Wei-Yi,Yi, Li-Li,Jing, Heng,Sheng, Li-Xin,Wan, Qin,Zhong, Ping-Fu,Fang, Hai-Lian,Ouyang, Hui,Xiao, Zhu-Ping,Zhu, Hai-Liang
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supporting information
p. 4145 - 4152
(2018/07/13)
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- Synthesis and luminescence properties of novel 8-hydroxyquinoline derivatives and their Eu(III) complexes
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Six novel 8-hydroxyquinoline derivatives were synthesized using 2-methyl-8-hydroxyquinoline and para-substituted phenol as the main starting materials, and were characterized by 1H nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet (UV) light analysis and infra-red (IR) light analysis. Their complexes with Eu(III) were also prepared and characterized by elemental analysis, molar conductivity, UV light analysis, IR light analysis, and thermogravimetric–differential thermal analysis (TG–DTA). The results showed that the ligand coordinated well with Eu(III) ions and had excellent thermal stability. The structure of the target complex was EuY1–6(NO3)3.2H2O. The luminescence properties of the target complexes were investigated, the results indicated that all target complexes had favorable luminescence properties and that the introduction of an electron-donating group could enhance the luminescence intensity of the corresponding complexes, but the addition of an electron-withdrawing group had the opposite effect. Among all the target complexes, the methoxy-substituted complex (–OCH3) had the highest fluorescence intensity and the nitro-substituted complex (–NO2) had the weakest fluorescence intensity. The results showed that 8-hydroxyquinoline derivatives had good energy transfer efficiency for the Eu(III) ion. All the target complexes had a relatively high fluorescence quantum yield. The fluorescence quantum yield of the complex EuY3(NO3)3.2H2O was highest among all target complexes and was up to 0.628. Because of excellent luminescence properties and thermal stabilities of the Eu(III) complexes, they could be used as promising candidate luminescent materials.
- Wu, Yongqiang,Guo, Tiantong,Shu, Dehua,Zhang, Wu,Luan, Fangfei,Shi, Ling,Guo, Dongcai
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p. 855 - 862
(2018/07/13)
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- Synthesis, Nematicidal Activity, and 3D-QSAR of Novel 1,3,4-Oxadiazole/ Thiadiazole Thioether Derivatives
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Forty one novel 1,3,4-oxadiazole/thiadiazole thioether derivatives containing phenoxy moiety were designed and synthesized. Bioassay demonstrated that some of them showed remarkable activities against Tylenchulus semipenetrans in vitro and in vivo. Compounds 20, 21, 35 and 39 showed excellent lethal activities after treatment for 48?h in vitro, with LC50 values of 13.4?±?1.8, 11.7?±?2.5, 13.7?±?2.4 and 13.3?±?1.1?mg·L–1, respectively, which were obviously superior to fosthiazate (49.1?±?2.8?mg·L–1) and avermectin (26.6?±?2.3?mg·L–1). Compound 21 can effectively control the citrus nematode disease caused by T. semipenetrans at 200?mg·L–1 in vivo with (68?±?3)% inhibitory effect, which was even better than that of avermectin ((63?±?2)%). The CoMFA and CoMSIA models of three-dimensional quantitative structure-activity relationships (3D-QSARs) were established. The compound 33 was designed based on the 3D-QSAR models with more vigorous nematicidal activities in vitro (LC50?=?9.8?±?1.4?mg·L–1) and in vivo ((70?±?5)%). These results demonstrated that compound 33 can be considered as a potential nematicide.
- Chen, Jixiang,Gan, Xiuhai,Yi, Chongfen,Wang, Shaobo,Yang, Yuyuan,He, Fangcheng,Hu, Deyu,Song, Baoan
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p. 939 - 944
(2018/09/22)
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- Synthesis and properties of coumarin derivatives and their terbium complexes
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A series of coumarin derivatives obtained from salicylaldehyde and phenol were synthesized. Their corresponding terbium complexes were prepared and characterized by elemental analysis, EDTA titrations, molar conductivity, UVvis spectra, IR spectra, and thermal analysis. The luminescent properties and electrochemical properties of the terbium complexes were also investigated. The results showed that all the terbium complexes exhibited characteristic emissions of terbium ions. The introduction of electron-donating groups can improve the luminescent properties, decrease the HOMO and LUMO energy levels of the terbium complex, while electron-withdrawing groups can weaken the luminescent properties, and increase the HOMO and LUMO energy levels of terbium complex.
- Meng, Defen,Xu, De,Li, Dong,Dai, Ming,Li, Guizhi,Guo, Dongcai
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p. 5269 - 5280
(2016/06/01)
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- Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents
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A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10 μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented.
- Zhong, Yan,Xu, Yi,Zhang, Ai-Xia,Li, Xiao-Feng,Xu, Zhao-Ying,Li, Ping,Wu, Bin
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supporting information
p. 2526 - 2530
(2016/07/07)
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- A stable and porous iridium(III)-porphyrin metal-organic framework: Synthesis, structure and catalysis
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Self-assembly of a new metalloporphyrin tetracarboxylic ligand Ir(TCPP)Cl (TCPP = tetrakis(4-carboxyphenyl)porphyrin) with ZrCl4 in the presence of benzoic acid leads to the formation of a three-dimensional (3D) iridium(III)-porphyrin metal-organic framework (Ir-PMOF) with the formula of [(Zr6(μ3-O)8(OH)2(H2O)10)2(Ir(TCPP)Cl)3]·solvents (Ir-PMOF-1(Zr)), which possesses square-shaped channels of 1.9 × 1.9 nm2 (atom-to-atom distances across opposite Ir metal atoms) in three orthogonal directions as disclosed by the single-crystal X-ray diffraction analysis. Ir-PMOF-1(Zr) represents the first MOF bearing a self-supporting iridium-porphyrin catalytic framework, featuring high porosity and stability. The catalytic tests disclose that the activated Ir-PMOF-1(Zr) can promote O-H insertion with a turnover frequency (TOF) up to 4260 h-1. Ir-PMOF-1(Zr) can be recycled and reused for 10 runs without significant loss of catalytic activity, and the total turnover number (TON) for O-H insertion after 10 successive runs reaches 875.
- Cui, Hao,Wang, Yingxia,Wang, Yanhu,Fan, Yan-Zhong,Zhang, Li,Su, Cheng-Yong
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p. 2203 - 2209
(2016/03/30)
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- Radical decarboxylative fluorination of aryloxyacetic acids using N-fluorobenzenesulfonimide and a photosensitizer
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Fluorinated methoxy arenes are emerging as important motifs in both agrochemicals and pharmaceuticals. A novel technique for the synthesis of monofluoromethoxy arenes through the direct fluorodecarboxylation of carboxylic acids was developed that uses photosensitizers and N-fluorobenzenesulfonimide (NFSI). Utilization of the oxidatively mild fluorine transfer agent NFSI enabled the synthesis of fluoromethyl ethers that were previously inaccessible with decarboxylative fluorinations performed with Selectfluor. Mechanistic studies are consistent with the photosensitizer effecting oxidation of the aryloxyacetic acid.
- Leung, Joe C. T.,Sammis, Glenn M.
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supporting information
p. 2197 - 2204
(2015/04/14)
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- Synthesis, Characterization and Properties of Novel Coumarin Derivatives and Their Europium Complexes
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Seven novel coumarin derivatives derived from salicylaldehyde and phenol were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their corresponding Eu(III) complexes having general formula EuL1-7(NO3)3·2H2O were successfully prepared and characterized by elemental analysis, EDTA titrimetric, molar conductivity, UV-Vis, FT-IR and thermal performance studies. The luminescence properties, fluorescence quantum yields and the electrochemical properties of the title complexes were investigated. The results showed that the title complexes exhibited characteristic emissions of europium ions and possessed relatively good fluorescence quantum yields. The luminescence intensity of the complex with bromine-substituted group is the strongest among all the title complexes. The introduction of electron-withdrawing groups can increase the luminescence properties and fluorescence quantum yields, decrease the HOMO and LUMO energy levels of the title europium complexes, but electron-withdrawing group conversely. And these title complexes may possibly be useful for studying in luminescent materials field.
- Yan, Dong,Li, Dong,Cheng, Guang,Yang, Zehui,Shi, Ling,Guo, Dongcai
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p. 849 - 859
(2015/08/24)
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- Synthesis and luminescence properties of pyrazolone derivatives and their terbium complexes
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Seven novel pyrazolone derivatives were synthesized and characterized by 1H NMR and 13C NMR spectra, mass spectra, infrared spectra and elemental analysis. Their terbium complexes were prepared and characterized by elemental analysis, EDTA titrimetric analysis, UV/vis spectra, infrared spectra and molar conductivity, as well as thermal analysis. The fluorescence properties and fluorescence quantum yields of the complexes were investigated at room temperature. The results indicated that pyrazolone derivatives had good energy-transfer efficiency for the terbium ion. All the terbium complexes emitted green fluorescence characteristic of terbium ions, possessed strong fluorescence intensity, and showed relatively high fluorescence quantum yields. Cyclic voltammograms of the terbium complexes were studied and the highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO) energy levels of these complexes were estimated.
- Xiao, Haihua,Jiang, Xi,Li, Dong,Wu, Limin,Zhang, Wu,Guo, Dongcai
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p. 677 - 685
(2015/12/04)
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- Synthesis of oxadiazole-morpholine derivatives and manifestation of the repressed CD31 Microvessel Density (MVD) as tumoral angiogenic parameters in Dalton's Lymphoma
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A series of oxadiazole derivatives possessing morpholine 6a-l were synthesized by nucleophilic substitution reaction of key intermediates [1,3,4]-oxadiazole-2-thiol derivatives 5a-l with 4-(2-chloroethyl) morpholine. Compounds 6a-l were evaluated for their in vitro and in vivo antitumor potential in Dalton's Lymphoma Ascites (DLA) tumor cells. Among 6a-l series, compound 6a with concentration ~8.5 μM have shown extensive cytotoxicity in vitro and 85% reduction in tumor volume in vivo, attributing an excellent anti-proliferative capability towards the cancer cells. Compound 6a has extensively inhibited the Microvessel Density (MVD) or tumoral neovasculature which was evident from the CD31 immuno staining and peritoneal H&E staining. The major reason for the antiproliferative activity of compound 6a was due to the repression of tumor vasculature.
- Al-Ghorbani, Mohammed,Vigneshwaran,Ranganatha, V. Lakshmi,Prabhakar,Khanum, Shaukath Ara
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p. 136 - 146
(2015/06/02)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 141-142
(2014/08/07)
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- 4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors
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A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthes
- Weiser, Patrick T.,Chang, Ching-Yi,McDonnell, Donald P.,Hanson, Robert N.
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p. 917 - 926
(2014/01/23)
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- Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents
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In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA enzyme. Highly active compound 5r (MIC 0.2 μg/mL) showed hydrogen bonding interactions with Tyr158 and NAD+ in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (rpred2) of 0.896 and 0.930, respectively.
- More, Uttam A.,Joshi, Shrinivas D.,Aminabhavi, Tejraj M.,Gadad, Andanappa K.,Nadagouda, Mallikarjuna N.,Kulkarni, Venkatrao H.
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p. 199 - 218
(2014/01/06)
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- Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group
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Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.
- Maingot, Lucie,Elbakali, Jamal,Dumont, Julie,Bosc, Damien,Cousaert, Nicolas,Urban, Agathe,Deglane, Gaelle,Villoutreix, Bruno,Nagase, Hideaki,Sperandio, Olivier,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 244 - 261
(2013/10/01)
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- Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships
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Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
- Polucci, Paolo,Magnaghi, Paola,Angiolini, Mauro,Asa, Daniela,Avanzi, Nilla,Badari, Alessandra,Bertrand, Jay,Casale, Elena,Cauteruccio, Silvia,Cirla, Alessandra,Cozzi, Liviana,Galvani, Arturo,Jackson, Peter K.,Liu, Yichin,Magnuson, Steven,Malgesini, Beatrice,Nuvoloni, Stefano,Orrenius, Christian,Sirtori, Federico Riccardi,Riceputi, Laura,Rizzi, Simona,Trucchi, Beatrice,O'Brien, Tom,Isacchi, Antonella,Donati, Daniele,D'Alessio, Roberto
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p. 437 - 450
(2013/04/10)
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- Development of hypoxia-inducible factor (HIF)-1α inhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia
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A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI50) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC50: 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC50: 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC50: 10.9 ± 0.63 μM).
- Nakamura, Hiroyuki,Yasui, Yuka,Maruyama, Minako,Minegishi, Hidemitsu,Ban, Hyun Seung,Sato, Shinichi
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p. 806 - 810
(2013/02/25)
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- Synthesis of substituted asymmetrical biphenyl amino esters as alpha helix mimetics
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As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this study, we describe synthetic methods for preparing
- Williams, Anna B.,Hanson, Robert N.
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experimental part
p. 5406 - 5414
(2012/09/08)
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- Synthesis and antimicrobial activity of phthalazines and pyridazines
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A new series of 2,3-dihydro phthalazine-1,4-diones, Va-b and 2,3,4,5-tetrahydro pyridazine-3,6-diones Vla-b were synthesized using p-chloro phenol and p-bromo phenol, as starting materials. The final compounds were prepared by reacting corresponding hydrazides with phthalic anhydride and succinic anhydride to get Va-b, Vla-b by fusion reaction. Structures of the synthesized compounds were confirmed on the basis of physical and spectral data (IR, 1H NMR and Mass). All the synthesized compounds were screened for their antimicrobial activity. Minimum inhibitory cone for the synthesized compounds were determined by using broth micro dil method. Among the synthesized compounds, compound Vb, having bromine at para position of the aromatic ring was found to be active at the lowest cone of 0.005 μM/ml against Gram positive bacteria Bacillus subtilis as compared to standard Ciprofloxacin, Norfloxacin and compound Vb was found active at the concentration of 0.005 μM/ml against fungi Candida albicans as compared to standard Fluconazole and Griseofulvin.
- Purohit, Shriram S.,Patil, Pavan A.
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p. 269 - 272
(2013/09/24)
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- Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2- (phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives
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An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC50 values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
- Sathisha,Khanum, Shaukath A.,Chandra, J.N. Narendra Sharath,Ayisha,Balaji,Marathe, Gopal K.,Gopal, Shubha,Rangappa
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experimental part
p. 211 - 220
(2011/03/17)
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- A specific protein disorder catalyzer of HIV-1 Nef
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The HIV-1 auxiliary protein Nef is required for the onset and progression of AIDS in HIV-1-infected persons. Here, we have deciphered the mode of action of a second-generation inhibitor of Nef, DLC27-14, presenting a competitive IC50 of ~16 μM measured by MALDI-TOF experiments. Thermal protein denaturation experiments revealed a negative effect on stability of Nef in the presence of a saturating concentration of the inhibitor. The destabilizing action of DLC27-14 was confirmed by a HIV protease-based experiment, in which the protease sensitivity of DLC27-14-bound Nef was three times as high as that of apo Nef. The only compatible docking modes of action for DLC27-14 suggest that DLC27-14 promotes an opening of two α-helices that would destabilize the Nef core domain. DLC27-14 thus acts as a specific protein disorder catalyzer that destabilizes the folded conformation of the protein. Our results open novel avenues toward the development of next-generation Nef inhibitors.
- Lugari, Adrien,Breuer, Sebastian,Coursindel, Thibault,Opi, Sandrine,Restouin, Audrey,Shi, Xiaoli,Nazabal, Alexis,Torbett, Bruce E.,Martinez, Jean,Collette, Yves,Parrot, Isabelle,Arold, Stefan T.,Morelli, Xavier
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supporting information; experimental part
p. 7401 - 7406
(2012/02/02)
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- (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors
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Structural modification of a compound discovered during screening using an HRE-dependent reporter assay has revealed a novel class of HIF-1 inhibitors, which potently inhibit the HIF-1α protein accumulation and its target gene expression under hypoxic conditions in human hepatocellular carcinoma Hep3B cells.
- Lee, Kyeong,Lee, Jeong Hyung,Boovanahalli, Shanthaveerappa K.,Jin, Yinglan,Lee, Mijeoung,Jin, Xuejun,Kim, Jin Hwan,Hong, Young-Soo,Lee, Jung Joon
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p. 1675 - 1684
(2008/02/01)
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- Fused pyridine derivatives
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The present provides a condensed pyridine compound (I) represented by the following formula: (wherein, R2represents ring A represents benzene ring, pyridine ring, thiophene ring or furan ring; and B represents its pharmaceutically acceptable salt or hydrates thereof, which is a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating or preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
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- Synthesis, Characterization, Spectral and Antifungal Properties of Some 5-Substituted-1,3,4-oxadiazole-2-thiones and Their Mannich Bases
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A series of 5-substituted aryloxymethyl-1,3,4-oxadiazole-2-thione (3a-e) and their Mannich bases 4-8 are synthesized and subjected to fungitoxic screening.The structures of these compounds are established on the basis of elemental analysis 1H-n.m.r. and mass spectral data.The mass spectral fragmentation pathways of these compounds are discussed.
- Holla, B. Shivarama,Kalluraya, Balakrishna,Nath, S. C.
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p. 549 - 557
(2007/10/02)
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- Sulphur- and oxygen-containing diaryl compounds
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The sulphur- and oxygen-containing diaryl compounds of the formula: STR1 in which A and B, which may be the same or different, represent O, S, SO or SO2, Alk is a C1 -C4 hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic amide group, OH, O-SO2 CH3, NH2, NHR1, NR1 R2, NHZOH, NHZNR1 R2, C(=NH)NH2, C(=NH)NHOH or 2-Δ2 -imidazolinyl, Z is a C2 -C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1 -C3 lower alkyl group, or together form, with the nitrogen atom to which they are linked, a N-heterocyclic group of 5 to 7 ring atoms which can be substituted and can comprise a second hetero-atom, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical, are useful pharmacological agents in the treatment of circulatory complaints such as cardio-vascular illnesses.
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