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Chemical Biology & Drug Design

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https://www.readbyqxmd.com/read/29777569/improving-metabolic-stability-with-deuterium-the-discovery-of-hwl-066-a-potent-and-long-acting-free-fatty-acid-receptor-1-agonists
#1
Chunxia Liu, Zheng Li, Wei Shi, Huilan Li, Nasi Wang, Yuxuan Dai, Chen Liao, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancing of glucose-stimulated insulin secretion. The FFA1 agonist GW9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of GW9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid affording compound 4 (HWL-066)...
May 18, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29770563/extending-the-scope-of-amantadine-drug-by-incorporation-of-phenolic-azo-schiff-bases-as-potent-selective-inhibitors-of-carbonic-anhydrase-ii-drug-likeness-and-binding-analysis
#2
Pervaiz Ali Channar, Aamer Saeed, Danish Shahzad, Fayaz Ali Larik, Mubashir Hassan, Hussain Raza, Qamar Abbas, Sung-Yum Seo
A series of Amantadine based azo Schiff base dyes 6a-6e have been synthesized and characterized by 1 H NMR and 13 C NMR and evaluated for their in vitro carbonic anhydrase II inhibition activity and antioxidant activity. All of the synthesized showed excellent carbonic inhibition. Compound 6b was found to be the most potent derivative in the series, the IC50 of 6b was found to be 0.0849 ± 0.00245μM (standard Acetazolamide IC50 =0.9975±0.049μM). The binding interactions of the most active analogs were confirmed through molecular docking studies...
May 16, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29767460/pyrimidine-based-pyrazoles-as-cyclin-dependent-kinase-2-inhibitors-design-synthesis-and-biological-evaluation
#3
Mayur K Vekariya, Rajesh H Vekariya, Pathik S Brahmkshatriya, Nisha K Shah
A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2-CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50 < 20 nM); which can be further optimized to have selectivity over other kinase isoforms...
May 16, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29745064/molecular-basis-of-benzimidazole-inhibitors-to-hepatitis-c-virus-envelope-glycoprotein
#4
Reaz Uddin, Kevin M Downard
The molecular basis for the inhibitory action of a benzimidazole inhibitor compound to hepatitis C virus (HCV) E1 envelope protein was examined computationally. Structures for the wild type E1 protein and 7 mutants were modelled using an ab initio protein structure prediction algorithm, and these models were docked with the benzimidazole inhibitor. Top ranked conformers for each docked structure were examined in the context of the putative function of the inhibitor that blocks fusion of the envelope protein to the host cells...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29745048/new-1-2-3-triazole-based-analogues-of-benznidazole-for-use-against-trypanosoma-cruzi-infection-in-vitro-and-in-vivo-evaluations
#5
Débora Inácio Leite, Fábio de Vasconcellos Fontes, Monica Macedo Bastos, Lucas Villas Boas Hoelz, Maria da Conceição Avelino Dias Bianco, Andressa Paula de Oliveira, Patricia Bernardino da Silva, Cristiane França da Silva, Denise da Gama Jean Batista, Aline Nefertiti Silva da Gama, Raiza Brandão Peres, Jose Daniel Figueroa Villar, Maria de Nazaré Correia Soeiro, Nubia Boechat
Chagas disease (CD) has spread throughout the world mainly because of the migration of infected individuals. In Brazil, only benznidazole (Bnz) is used; however, it is toxic and not active in the chronic phase, and cases of resistance are described. This work aimed at the synthesis and the trypanocidal evaluation in vitro and in vivo of six new Bnz analogues (3-8). They were designed by exploring the bioisosteric substitution between the amide group contained in Bnz and the 1,2,3-triazole ring. All the compounds were synthesized in good yields...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29745031/trypanosoma-cruzi-biochemical-changes-and-cell-death-induced-by-an-organometallic-platinum-based-compound
#6
M Florencia Mosquillo, Lucía Bilbao, Fabricio Hernández, Florencia Tissot, Dinorah Gambino, Beatriz Garat, Leticia Pérez-Díaz
Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug resistant strains underscores the need of new drugs. Platinum-based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolate-1-oxide Pt(II) hexafluorophosphate, Pt-dppf-mpo, was studied on T. cruzi. A promising anti-trypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro cultured mammal cells...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29745030/synthesis-and-biological-evaluation-of-novel-n-aryl-%C3%AF-benzoazol-2-yl-sulfanylalkanamides-as-dual-inhibitors-of-%C3%AE-glucosidase-and-protein-tyrosine-phosphatase-1b
#7
Mei-Yan Wang, Xian-Chao Cheng, Xiu-Bo Chen, Yu Li, Lan-Lan Zang, Yu-Qing Duan, Ming-Zhu Chen, Peng Yu, Hua Sun, Run-Ling Wang
α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α-glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides were synthesized and assayed for their α-glucosidase and PTP1B inhibitory activities, respectively...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29729071/syntheses-and-evaluation-of-68-ga-and-153-sm-labeled-dota-conjugated-bisphosphonate-ligand-for-potential-use-in-detection-of-skeletal-metastases-and-management-of-pain-arising-from-skeletal-metastases
#8
Sudipta Chakraborty, Dibakar Goswami, Rubel Chakravarty, Shahiralam Khan Mohammed, H D Sarma, Ashutosh Dash
This article reports the syntheses and evaluation of 68 Ga- and 153 Sm-complexes of a new DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated geminal bisphosphonate, DOTA-Bn-SCN-BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeketal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three step reaction scheme. Gallium-68- and 153 Sm-complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate buffered slaine (PBS) and human serum...
May 5, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29729083/hydrocortisone-inhibition-of-wild-type-and-%C3%AE-d200q-nicotinic-acetylcholine-receptors
#9
Beata Dworakowska, Ewa Nurowska, Krzysztof Dołowy
Short-term treatment with large doses of corticosteroids can result in acute weakness of muscles in processes that have not yet been fully characterized. Corticosteroids have been shown to exert direct inhibitory action on the muscle-type nicotinic acetylcholine receptor (AChR) and therefore can promote pharmacological muscle denervation. The mechanism of hydrocortisone (HC) blockage of AChR has not been fully established yet. It is uncommon for an electrically neutral molecule, e.g. HC, to induce voltage-dependent changes in AChR kinetics...
May 4, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29729080/discovery-of-benzimidazole-based-l-mexicana-cysteine-protease-cpb2-8%C3%AE-cte-inhibitors-as-potential-therapeutics-for-leishmaniasis
#10
Laura De Luca, Stefania Ferro, Maria Rosa Buemi, Anna-Maria Monforte, Rosaria Gitto, Tanja Schirmeister, Louis Maes, Antonio Rescifina, Nicola Micale
Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug-resistance or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a-d) showing affinity in the submicromolar range (Ki = 0...
May 4, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29722184/synthesis-and-antibacterial-activities-of-novel-pleuromutilin-derivatives-bearing-an-aminothiophenol-moiety
#11
Zhao-Sheng Zhang, Yun-Zhen Huang, Jian Luo, Zhen Jin, Ya-Hong Liu, You-Zhi Tang
A series of novel thioether pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC25922) were evaluated. The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA...
May 3, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29722203/one-pot-synthesis-and-antiproliferative-activity-of-novel-double-modified-derivatives-of-the-polyether-ionophore-monensin-a
#12
Greta Klejborowska, Maj Ewa, Joanna Wietrzyk, Joanna Stefańska, Adam Huczyński
Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity. New MON derivatives such as double-modified ester-carbonates and double-modified amide-carbonates were obtained by a new and efficient one-pot synthesis with triphosgene as the activating reagent and the respective alcohol or amine. All new derivatives were tested for their antiproliferative activity against two drug-sensitive (MES-SA, LoVo) and two drug-resistant (MES-SA/DX5, LoVo/DX) cancer cell lines, and were also studied for their antimicrobial activity against different Staphylococcus aureus and Staphylococcus epidermidis bacterial strains...
May 2, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29722179/co-administration-of-kla-tat-peptide-and-irgd-to-enhance-the-permeability-on-a549-3d-multiple-sphere-cells-and-accumulation-on-xenograft-mice
#13
Cuihua Hu, Xiaolong Chen, Yibing Huang, Yuxin Chen
To enhance the anticancer activity, tumor penetration ability of the hybrid anticancer peptide, in this study, a TAT (RKKRRQRRR) peptide modified kla peptide (KLAKLAKKLAKLAK, with all D-amino acids), named kla-TAT, was co-administrated with the homing/penetrating peptide iRGD which could enhance the permeability of chemical drug in solid tumor and tumor vessel by co-administration. In this study, the non-small cell lung cancer (NSCLC) A549 cell line with the iRGD targeting receptor neuropilin-1 (NRP-1) high expression was selected to establish the 2D monolayer cell, 3D multiple cell spheroids and xenograft mice model...
May 2, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29718569/grp78-targeted-in-silico-virtual-screening-of-novel-anticancer-agents
#14
Ambily Nath Indu Viswanath, Ji Woong Lim, Seon Hee Seo, Jae Yeol Lee, Sang Min Lim, Ae Nim Pae
Overexpression of GRP78 in a variety of cancers such as glioblastoma, leukaemia, lung, prostate, breast, gastric, and colon makes it a prime target for anticancer drug development. Present study reports GRP78-based design of novel anticancer agents using in silico methods. As a first step towards the work, the interactions between GRP78 and 15 known ligands were modeled by docking simulation. The docked complex, GRP78-13, superior to other compounds with respect to its experimental activity and energy descriptors, was deduced into a structure-based pharmacophore...
May 2, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29710404/design-synthesis-and-biological-evaluation-of-structurally-constrained-hybrid-analogues-containing-ropinirole-moiety-as-a-novel-class-of-potent-and-selective-dopamine-d3-receptor-ligands
#15
Benhua Zhou, Kwon Ho Hong, Min Ji, Jin Cai
Two series of hybrid analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined (using the method of radioligand binding assay). Compared to comparator agent BP897, compounds 2a and 2c were found to demonstrate a considerable binding affinity and selectivity for D3 receptor, and especially compound 2h was similarly potent and more selective D3R ligand than BP897, a positive reference. Thus they may provide valuable information for the discovery and development of highly potent dopamine D3 receptor ligands with outstanding selectivity...
April 30, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29704399/design-synthesis-chalcone-derivatives-as-adipor-agonist-for-type-2-diabetes
#16
Panhu Zhu, Weijun Huang, Jiaming Li, Xiaodong Ma, Mengqi Hu, Yujun Wang, Qinlong Xu, Xianna Wang
Two structurally novel series of chalcone derivatives were designed and synthesized as potential agents against type 2 diabetes. As a result of the antidiabetic biological evaluation in streptozotocin (STZ) induced type 2 diabetes animal model, 13e, 13g and 19f showed more significant reduction in serum Glu, TG, TC levels by contrast to the positive control AdipoRon. In addition to upregulating the expression of AdipoR1 and AdipoR2, 13e and 19f treatment also increased expression of AMPK and PPAR-α. Taken together, these results suggested that 13e and 19f might be a promising compounds for type 2 diabetes treatment...
April 28, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29693318/synthesis-activity-and-docking-studies-of-eugenol-based-glucosides-as-new-agents-against-candida-sp
#17
Taciane Maíra Magalhães Hipólito, Guilherme Tadeu Lemos Bastos, Thúlio Wliandon Lemos Barbosa, Thiago Belarmino de Souza, Luiz Felipe Leomil Coelho, Amanda Latércia Tranches Dias, Ihosvany Camps Rodríguez, Marcelo Henrique Dos Santos, Danielle Ferreira Dias, Lucas Lopardi Franco, Diogo Teixeira Carvalho
Seventeen new synthetic derivatives of eugenol (6, 8-15 and 8'-15') were planned following literature reports on antifungal activities of nitroeugenol and eugenol glucoside. The anti-Candida activity of these compounds was investigated by in vitro assay and the cytotoxicity evaluation was performed with the most active compounds. The peracetylated glucosides presented better biological results than their hydroxylated analogues. The glucoside 11, a 4-nitrobenzamide, showed the best potency (MIC50 range 11.0-151...
April 25, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29682907/effects-of-increasing-hydrophobicity-by-n-terminal-myristoylation-on-the-antibacterial-and-hemolytic-activities-of-the-c-terminal-cationic-segments-of-human-%C3%AE-defensins-1-3
#18
Krishnakumari Viswanatha, Ankeeta Guru, Harikrishna Adicherla, Nagaraj Ramakrishnan
Analogs of the cationic C-terminal segments of human-β-defensins HBD1-3, Phd1-3 with a single disulfide bond, exhibited comparable antimicrobial activity that were salt sensitive. They did not show hemolytic activity. In the present study, N-terminal myristoylation was carried out on Phd1-3 to examine whether increasing hydrophobicity would result in improved antibacterial activity. The antibacterial activity of the oxidized myristoylated peptides MPhd1-3 and their reduced forms MPhd1r-3r was determined. These peptides showed enhanced antibacterial activity as compared to Phd1-3, on mid-log phase and stationary phase of Staphylococcus aureus and Escherichia coli, except MPhd1r-3r that were inactive on stationary phase E...
April 23, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29682904/molecular-description-of-%C3%AE-keto-based-inhibitors-of-cruzain-with-activity-against-chagas-disease-combining-3d-qsar-studies-and-molecular-dynamics
#19
Ádria P B Saraiva, Ricardo M Miranda, Renan P P Valente, Jéssica O Araújo, Rutelene N B Souza, Clauber H S Costa, Amanda R S Oliveira, Michell O Almeida, Antonio F Figueiredo, João E V Ferreira, Cláudio Nahum Alves, Kathia M Honorio
In this work a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q2 and r2 ) for the models were, respectively, 0...
April 22, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29679451/dual-protected-amino-acid-derivatives-as-new-antitubercular-agents
#20
LETTER
Pedro P de Castro, Débora L Campos, Fernando R Pavan, Giovanni W Amarante
Tuberculosis is an infectious disease with high incidence and growing drug-resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated towards a M. tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC-5 cells (ATCC CCL-171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity...
April 20, 2018: Chemical Biology & Drug Design
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