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Chemical Biology & Drug Design

Yuanyuan Yi, Luhong Wang, Dan Zhao, Shanshan Huang, Changyuan Wang, Zhihao Liu, Huijun Sun, Kexin Liu, Xiaodong Ma, Yanxia Li
A new class of thiodiphenylpyrimidine analogues (Thio-DPPY) were synthesized as potent and selective EGFR T790M inhibitors to overcome gefitinib resistance in non-small cell lung cancer (NSCLC). This structural optimization led to the identification of two potent EGFRT 790M/L858R inhibitors, 14a and 14e, which possess IC50 values of 27.5 and 9.1 nM, respectively. Moreover, compounds 14a (SI > 36.4) and 14e (SI > 109.9) exhibited high selectivity and low activity against the wild type EGFR (IC50 > 1000 nM)...
July 20, 2018: Chemical Biology & Drug Design
Bhawna Vyas, Shalki Choudhary, Pankaj Kumar Singh, Baldev Singh, Renu Bahadur, Ashok Kumar Malik, Om Silakari
Diabetic complications follow multiple pathophysiological pathways involving aldose reductase (ALR2) mediated polyol pathway, advanced glycation end products (AGEs) and reactive oxygen species formation. Literature suggests ALR2 inhibitors such as Epalrestat to possess significant potential in retinopathy and neuropathy. Thus in this study multiple pathophysiology directed molecules targeting ALR2,AGEs and free radicals formation were designed using in-silico techniques. Initially, database was screened via in-silico tools to obtain hitswith affinity for the catalytic domain of ALR2...
July 20, 2018: Chemical Biology & Drug Design
Shasha Liu, Xiaoxia Liu, Xun Zhang, Meiyun Shi, Hecheng Wang, Yajun Liu
Crizotinib, a drug for anaplastic lymphoma kinase (ALK) positive and c-ros oncogene 1 receptor tyrosine kinase (ROS1) positive non-small cell lung cancer (NSCLC), was structurally optimized via a strategy of structure based fragment replacing. Computational study showed it was beneficial for interaction of crizotinib and ALK to increase the distance between pyridyl ring and phenyl ring in crizotinib, and thus a series of novel glycol diaryl ethers were synthesized. The in vitro anti-tumor activity of synthesized compounds was studied in NSCLC cell line H2228 and neurobalstoma cell line SH-SY5Y...
July 19, 2018: Chemical Biology & Drug Design
Majdi M Bkhaitan, Mohammed Alarjah, Agha Zeeshan Mirza, Ashraf N Abdalla, Hamdi M El-Said, Hani S Faidah
Two series of metronidazole derivatives (ester derivatives and ether derivatives) were prepared reacting metronidazole and its acetic acid oxidized form with menthol, thymol, carvacrol and, eugenol. Both series of compounds were tested in vitro against two strains of H. pylori (the ATCC 26695 and P12), and one strain of Clostridium (Clostridium perfringens). Most of the prepared compounds showed biological activity against the targeted bacteria. Compound 11 was highly active against all tested bacterial strains, especially against P12 with IC50 0...
July 18, 2018: Chemical Biology & Drug Design
Limin Huang, Di Wei, Zibo Wu, Yajing Hou, Yitong Xie, Zhenru Liu, Cheng Wang, Delu Che, Yibo Lei, Huaizhen He
A fluorescent probe (Fluo-HMF) was developed via introduction of a furfural moiety into the fluorescein molecular skeleton, aiming at specially labeling cell membrane of mast cells. To illustrate its specificity, we designed and synthesized a series of fluorescent compounds based on fluorescein molecular skeleton. The fluorescent properties of Fluo-HMF were investigated, which were in accordance with theoretical calculations. Compared with other fluorescein derivatives, Fluo-HMF could specially label RBL-2H3 cells...
July 18, 2018: Chemical Biology & Drug Design
Johan A Kers, R Eryl Sharp, Sheela Muley, Melissa Mayo, Jeffrey Colbeck, Yihui Zhu, Anthony W DeFusco, Jae H Park, Martin Handfield
Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Saturation mutagenesis was employed to substitute every amino acid of a lantibiotic called mutacin 1140 (MU1140), creating an unbiased expression library of 418 variants that was used to study the permissiveness to mutagenesis and the "drugability" of several compounds. Contrasting previous reports, the results from this study supported that not all residues involved in lanthionine bridge formation were critical for maintaining optimal activity...
July 16, 2018: Chemical Biology & Drug Design
Siyabonga I Maphumulo, Amit K Halder, Thavendran Govender, Sibusiso Maseko, Glenn E M Maguire, Bahareh Honarparvar, Hendrik G Kruger
HIV-1 protease (HIV PR) is considered one of the most attractive targets for the treatment of HIV and the impact of flap dynamics of HIV PR on the binding affinities of protease inhibitors (PIs) is one of the crucial ongoing research field. Recently, our research group evaluated the binding affinities of different FDA approved PIs against the South African HIV-1 subtype C (C-SA) protease (PR). The CSA- HIV PR displayed weaker binding affinity for most of the clinical PIs compared to HIV-1 B subtype for West and Central Europe, the Americas...
July 13, 2018: Chemical Biology & Drug Design
K Pratima, N Goud, Arifuddin Mohammed, Gayathri Ramamoorthy, Ragamanvitha Ananthathatmula, Mukesh Doble, Arshad Rizvi, Sharmista Banerjee, Ravi Alvala, Mallika Alvala
The rising multidrug-resistant Mycobacterium tuberculosis (Mtb) strain made current anti-TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity...
July 13, 2018: Chemical Biology & Drug Design
Guilherme Andrade Brancaglion, André Eidi Toyota, José Vaz Cardoso Machado, Antônio Ávila Fernandes Júnior, Alberto Thalison Silveira, Diego Fernandes Vilas Boas, Elda Gonçalves Dos Santos, Ivo Santana Caldas, Diogo Teixeira Carvalho
Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas' disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against T. cruzi epimastigotas. Then we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC50 28 ± 3 μM) similar to that of benznidazole (IC50 25 ± 10 μM)...
July 11, 2018: Chemical Biology & Drug Design
Keigo Gohda
Endpoint methods using continuum-solvent models are widely used to estimate protein-ligand affinity. A recently developed method, MM/3D-RISM, estimates the solvation energy using statistical mechanics by 3D-RISM. This method is theoretically expected to accurately describe solvation effects and to also be less dependent on protein-ligand systems. In this study, we examined the performance of MM/3D-RISM for a set of α-thrombin inhibitors with a non-congeneric series of ligands, containing three diverse chemical scaffolds...
July 1, 2018: Chemical Biology & Drug Design
Mohamed Touaibia, Martin J G Hébert, Natalie A Levesque, Jérémie A Doiron, Marco S Doucet, Jacques Jean-François, Marc Cormier, Luc H Boudreau, Marc E Surette
Given the hepatotoxicity and an unfavourable pharmacokinetic profile of Zileuton (Zyflo® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of fourteen phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated...
June 28, 2018: Chemical Biology & Drug Design
Kyra Gillard, Heather B Miller, Meghan S Blackledge
Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of recurrent infections in humans including endocarditis, pneumonia, and toxic shock syndrome. Novel therapeutics to treat MRSA and other resistant bacteria are urgently needed. Adjuvant therapy, which uses a non-toxic compound to repotentiate the toxic effects of an existing antibiotic, is an attractive response to the growing resistance crisis. Herein we describe the evaluation of structurally-related, FDA-approved tricyclic amine antidepressants that selectively repotentiate MRSA to β-lactam antibiotics...
June 28, 2018: Chemical Biology & Drug Design
Thaís Boulhosa Barros da Silva, Marta Chagas Monteiro, Rosivaldo Dos Santos Borges, Tainá Guimarães Barros, Agnaldo da Silva Carneiro, Carlos Augusto Lima Barros
The Penicillin Binding Proteins (PBPs) are important biological target for new antibacterial drugs development. This study focused on molecular interaction between cefoxitin and the Escherichia coli PBP5 by molecular dynamics (MD) by using hybrid quantum mechanics/molecular mechanics (QM/MM) simulations approach, searching to develop a computational simulations prototype method on antimicrobial susceptibility of gram-negative bacteria against antibiotics. E. coli ATCC 8739 strain susceptibility for the drugs used in the antimicrobial susceptibility testing and selection of bioactive molecules against resistant strain...
June 25, 2018: Chemical Biology & Drug Design
David Murphy, Pedro Reche, Darren R Flower
Dengue virus affects approximately 130 countries. 25% of infections result in febrile, self-limiting illness; heterotypic infection results in potentially fatal Dengue Haemorrhagic Fever or Dengue Shock Syndrome. Only one vaccine is currently available. Its efficacy is very variable. Thus, to target Dengue, we used an innovative immunoinformatic protocol to design a putative epitope ensemble vaccine by selecting an optimal set of highly-conserved epitopes with experimentally-verified immunogenicity. From 1597 CD4+ and MHC II epitopes, 6 MHC Class I epitopes (RAVHADMGYW, GPWHLGKLEM, GLYGNGVVTK, NMIIMDEAHF, KTWAYHGSY, WAYHGSYEV) and 9 MHC Class II epitopes (LAKAIFKLTYQNKVV, GKIVGLYGNGVVTTS, AAIFMTATPPGSVEA, AAIFMTATPPGTADA, GKTVWFVPSIKAGND, KFWNTTIAVSMANIF, RAIWYMWLGARYLEF, VGTYGLNTFTNMEVQ, WTLMYFHRRDLRLAA) were selected; this candidate vaccine achieved a world population coverage of 92...
June 21, 2018: Chemical Biology & Drug Design
Run-Ze Li, Xing-Xing Fan, Dan-Feng Shi, Guo-Yuan Zhu, Yu-Wei Wang, Lian-Xiang Luo, Hu-Dan Pan, Xiao-Jun Yao, Elaine Lai-Han Leung, Liang Liu
OBJECTIVE: Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore we aimed to identify new compounds that might act as Pyruvate kinase M2 isoform (PKM2) activators and to investigate their anti-cancer efficacy in non-small cell lung cancer (NSCLC) cells...
June 21, 2018: Chemical Biology & Drug Design
Yunyun Zhou, Wei Wei, Liangliang Zhu, Yuxin Li, Zhengming Li
Anthranilic diamides is a class of insecticides target at ryanodine receptors (RyRs). To discover potent insecticides targeting at RyRs, a series of novel anthranilic diamides with a diacylhydrazine bridge were designed and synthesized. Their insecticidal activities were evaluated and a preliminary structure-activity relationship (SAR) was summarized. In particular, compound 5g exhibited good lethality against oriental armyworm (Mythimna separata) at a concentration of 5 mg/L. The calcium-imaging experimental results indicated that the compound 5g can serve as effective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata (Walker) and Spodoptera exigua (Hübner), which probably activated the RyRs on the ER membrane...
June 20, 2018: Chemical Biology & Drug Design
Rabia Qamar, Aamer Saeed, Fayaz Ali Larik, Qamar Abbas, Mubashir Hassan, Hussain Raza, Sung-Yum Seo
A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (3a-k) have been synthesized from 1,3-oxazine-5-carbonitriles (2a-k). The protocol represents an efficient, facile and novel route from easily available precursors to unprecedented structures that share 1,3-oxazine and tetrazole motifs of utmost value. All the synthesized compounds (3a-k) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3-oxazine-tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2-bromophenyl moiety was the most potent among the series with IC50 value 0...
June 20, 2018: Chemical Biology & Drug Design
Keshab M Bairagi, Katharigatta N Venugopala, Pradip Kumar Mondal, Raquel M Gleiser, Deepak Chopra, Daniel García, Bharti Odhav, Susanta K Nayak
A series of methyl or ethyl 4-(substitutedphenyl/pyridyl)-6-methyl-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (HPM) analogues 4a-g was synthesized and evaluated for larvicidal activity against Anopheles arabiensis. These newly synthesized compounds were characterized by spectral studies such as FT-IR, NMR (1 H and 13 C), LC-MS and elemental analysis. The conformational features and supramolecular assembly of molecules 4a, 4b and 4e were further analyzed from single crystal X-ray study. The larvicidal activity of these tetrahydropyrimidine pharmacophore series were analyzed based on their relative substituent's...
June 20, 2018: Chemical Biology & Drug Design
Xingxing Dai, Ran Wang, Zhimin Wu, Shujuan Guo, Chang Yang, Lina Ma, Liping Chen, Xinyuan Shi, Yanjiang Qiao
Borneol (BO) and menthol (MEN) are two widely used natural permeation enhancers in the transdermal drug delivery system. In previous studies, their permeation enhancement effects and mechanisms of action on the hydrophobic drug osthole (logP=3.8) and hydrophilic drug 5-fluorouracil (logP=-0.9) have been studied. In this study, ligustrazine (LTZ), whose logP is 1.3, was used as a model drug to provide a comprehensive understanding of the influence of its logP on the permeation-enhancing effects of BO and MEN...
June 20, 2018: Chemical Biology & Drug Design
Nikita Devnarain, Mahmoud E S Soliman
The global threat of the Zika virus to humanity is real. Innovative and potent anti-Zika virus drugs are still at large, due to the lack of anti-Zika virus drugs that have passed phase 1 trials. Experimental research has revealed novel inhibitors of Zika virus NS5 methyltransferase enzyme. This study has taken a step further to provide insight into the molecular dynamics of Zika virus and inhibitor binding, which have not been established experimentally. Movements of the methyltransferase binding site loops have a large role to play in the methylation of the viral mRNA cap, which is essential for Zika virus replication...
June 20, 2018: Chemical Biology & Drug Design
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