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Chemical Biology & Drug Design

Pooja S P, Anu R M, Lalitha Biswas, Pavithran K, C Gopi Mohan
Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure-based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors) i.e. one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings...
March 17, 2017: Chemical Biology & Drug Design
Patrícia S Guerreiro, Eduardo Corvacho, João G Costa, Nuno Saraiva, Ana Sofia Fernandes, Matilde Castro, Joana P Miranda, Nuno G Oliveira
The human apurinic/apyrimidinic endonuclease 1 (APE1) is an ubiquitous multifunctional DNA repair enzyme and a redox signalling protein. Our work addressed the inhibition of APE1 redox function using E3330, as single agent or in combination with docetaxel (DTX), in human breast cancer MDA-MB-231 cells. E3330 decreased the colony formation of DTX-treated cells. In addition, E3330 alone significantly reduced the collective cell migration as assessed by the wound healing assay whereas the combined treatment decreased chemoinvasion...
March 17, 2017: Chemical Biology & Drug Design
Arun Divakar Mathiyazhagan, Sivakumar Shanmugam
A novel substituted pyrenoylpyrroles was synthesized by the reaction of pyrenoyl chalcone, TosMIC and methyl iodide under mild condition. All the synthesized compounds were screened for their bioactivity and the MIC was determined, among which few compounds showed moderate antibacterial activity towards gram-positive as well as negative bacteria. Further, cytotoxicity assay ascertained that these compounds were non-toxic to mammalian cells as well. The pyrene chromophore in the synthesized compounds (3a-e) and (5a-e) is responsible for the good photophysical properties which have an absorbance at λ 340 nm and emission at λ 410 nm...
March 17, 2017: Chemical Biology & Drug Design
Yue-Hui Zhang, Jia Song, Jing Zhang, Jiang Shao
The IL-1β gene is currently topic of interest for its important role in the pathogenesis of intervertebral disc degeneration. The new sequencing technology makes it crucial to study the effects of variants in IL-1β. Thus, 714 IL-1β variants with evidence supporting were collected from the EMBL database. Among them, 62 were nonsynonymous single nucleotide variants (nsSNVs). Furthermore, six common nsSNVs were predicted to have damaging effects by SIFT, PolyPhen, PROVEAN and SNPs&GO. Based on the constructed three-dimensional structure of pro-IL-1β, rs375479974 with a mutation of Phe to Ser was proposed to reduce the stability of the pro-IL-1β protein...
March 15, 2017: Chemical Biology & Drug Design
Fucheng Song, Lianhua Cui, Jinmei Piao, Hui Liang, Hongzong Si, Yunbo Duan, Honglin Zhai
Quantitative structure-activity relationship (QSAR) studies were performed on a series of 5-Arylidene-2thioxoimidazolidin-4-ones derivatives as the inhibitors of perforin, and to gain insights about the structural determinants for designing new drug molecules. The heuristic method (HM) could explore the descriptors responsible for bioactivity and gain a best linear model with R(2) 0.82. Gene expression programming (GEP) method generated a novel nonlinear function model with R(2) 0.92 for training set, and R(2) 0...
March 14, 2017: Chemical Biology & Drug Design
Utsab Debnath, Prachi Kumar, Aakanksha Agarwal, Ajay Kesharwani, Satish K Gupta, Seturam B Katti
An in silico method has been used to discover N-hydroxy substituted 2-aryl acetamide analogues as a new class of HIV-1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV-1 integrase inhibitors...
March 13, 2017: Chemical Biology & Drug Design
Lavanya Mallu, Dhakshanamurthy Thirumalai, Indira Viswambaran Asharani
Various S-methylphenyl substituted acridine-1,8-dione series (4a-i) were synthesized through a one-pot cascade synthetic approach involving the reaction of 4-(methylthio)benzaldehyde and dimedone with a variety of amines as nitrogen source under reflux in ethanol. All the synthesized derivatives were characterized by using spectroscopic methods. In-vitro evaluations of anti-inflammatory and anti-diabetic efficacies of all the synthesized compounds were investigated. The anti-inflammatory results infer that the compounds 4c and 4d are showing excellent activity with an inhibition percentage of 80...
March 13, 2017: Chemical Biology & Drug Design
Travis Korosh, Emmanuel Bujans, Mary Morada, Canan Karaalioglu, Jean Jacques Vanden Eynde, Annie Mayence, Tien L Huang, Nigel Yarlett
A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to C10 H20 ) containing a meta (m) or para (p) benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole susceptible (C1) and refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propadiylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) towards T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μM compared to 145 μM)...
March 10, 2017: Chemical Biology & Drug Design
Mirian Elisa Rodrigues Guerra, Valmir Fadel, Vinícius Gonçalves Maltarollo, Gisele Baldissera, Kathia Maria Honorio, José Roberto Ruggiero, Marcia Perez Dos Santos Cabrera
Leishmaniasis, a protozoan-caused disease, requires alternative treatments with minimized side effects and less prone to resistance development. Antimicrobial peptides represent a possible choice to be developed. We report on the prospection of structural parameters of 23 helical antimicrobial and leishmanicidal peptides as a tool for modeling and predicting the activity of new peptides. This investigation is based on molecular dynamic simulations (MD) in mimetic membrane environment, since most of these peptides share the feature of interacting with phospholipid bilayers...
March 7, 2017: Chemical Biology & Drug Design
Yasodakrishna Sajja, Sowmya Vanguru, Hanmanth Reddy Vulupala, Lingaiah Nagarapu, Perumal Yogeswari, Dharmarajan Sriram, Jagadeesh Babu Nanubolu
A new anti-tubercular agents, benzo[6,7]cyclohepta[1,2-b]pyridine -1,3,4- oxadiazole hybrids (6a-o) have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene (DIB) and characterized by IR,(1) H NMR,(13) C NMR, HRMS and further confirmed by X-ray analysis. All the newly synthesized compounds 4a-o evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1...
March 7, 2017: Chemical Biology & Drug Design
Neelam Kumari, Nidhi Chadha, Pooja Srivastava, Lokesh Chandra Mishra, Sunita Bhagat, Anil K Mishra, Anjani K Tiwari
We have synthesized six new congeners of acetamido-benzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8 ± 1.2 nM) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phenylacetamide, (NBMP). NBMP was synthesised by suzuki coupling reaction between 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid. Computational docking and simulation studies showed not much impact of intersubject variability on binding which is one of the major drawbacks of several TSPO ligands...
March 7, 2017: Chemical Biology & Drug Design
Glaécia A N Pereira, Gisele C Souza, Lourivaldo S Santos, Lauro E S Barata, Carla C F Meneses, Antoniana U Krettli, Cláudio Tadeu Daniel-Ribeiro, Cláudio Nahum Alves
The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors has left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and Anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and, (iii) for intermolecular interaction with the P...
February 28, 2017: Chemical Biology & Drug Design
Nikolaos Lougiakis, Efseveia Frakolaki, Panagiota Karmou, Nicole Pouli, Panagiotis Marakos, Vanesa Madan, Ralf Bartenschlager, Niki Vassilaki
A series of new tricyclic nucleosides were synthesized and evaluated as Hepatitis C virus (HCV) replication inhibitors. Initial screening in a HCV replicon system, derived from a genotype 1b isolate, identified 9-benzylamino-3-(β-D-ribofuranosyl)-3H-imidazo[4',5':5,6]pyrido[2,3-b]pyrazine (15d) as the most potent analogue. Comparative assessment of 15d activity against HCV full-length viruses or subgenomic replicons derived from genotype 1 - 4 revealed a specificity of the compound for genotypes 1 and 3. Surprisingly, resistance mutations selected against 15d were mapped to domains II and III of the nonstructural protein 5A (NS5A), but not to the RNA-dependent RNA polymerase residing in NS5B...
February 28, 2017: Chemical Biology & Drug Design
Xiao-Cai Wu, Shou-Hua Wang, Hong-Hui Ou, Bing Zhu, Yong Zhu, Qi Zhang, Yang Yang, Hua Li
The expression pattern and biological role of long non-coding RNA (lncRNA) in cancer has been reported to be involved in many cancers. Here we report the expression and biological role of a newly discovered lncRNA NmrA-like family domain containing 1 pseudogene (Loc344887) in gallbladder cancer (GBC). In this study, we found that the expression of Loc344887 was significantly elevated in GBC tissues and cell lines when compared with matched normal tissues and normal epithelial bile duct cell line, respectively...
February 28, 2017: Chemical Biology & Drug Design
Liangyu Zhang, Zelong Fu, Xia Li, Haitao Tang, Jiesi Luo, Dehui Zhang, Yongzhi Zhang, Zhiyang Han, Mingzhu Yin
Breast cancer is one for the most invasive cancer type in female population. The functional activity of transformation growth factor-activated factor 1 (TAK1) in breast cancer progression increasingly attracts attention since it provides a potential target for anti-breast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells...
February 21, 2017: Chemical Biology & Drug Design
Hua-Li Qin, Jing Leng, Bahaa G M Youssif, Muhammad Wahab Amjad, Maria Abdul Ghafoor Raja, Muhammad Ajaz Hussain, Zahid Hussain, Syeda Naveed Kazmi, Syed Nasir Abbas Bukhari
The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship...
February 10, 2017: Chemical Biology & Drug Design
Mahmoud S Ahmed, Fardous El-Senduny, Jessica Taylor, Fathi T Halaweish
Assembly of Cucurbitacin inspired estrone analogs have been previously synthesized and screened against melanoma cell lines. Further synthetic optimization was executed via installation of Azide polar functional moiety across 23, 24 α, β-unsaturated ketone side chain using Michael addition reaction. This was followed by biological screening against melanoma cell lines employing MTT assay, in-cell based ELISA assay, and western blot analysis to monitor the potential of the synthesized analogs to inhibit the phosphorylated ERK levels...
February 7, 2017: Chemical Biology & Drug Design
Sanaz Ebrahimi Samani, Zahra Seraj, Hossein Naderimanesh, Khosro Khajeh, Ahmad Reza Esmaeili Rastaghi, Taher Droudi, Peirhosein Kolivand, Hadi Kazemi, S Mohsen Asghari
Whereas several anticancer peptides are in different stages of clinical development, their administration is limited by fast elimination from the systemic circulation. Peptide loading on nano-carriers can pave the way for their future application. We have recently indicated that a disulfide loop rather than a Zn-binding loop improves the antiangiogenic and antitumor activities of the N-terminal fragment of endostatin. In this study, chitosan nanoparticles (CS NPs) are used for the controlled release of the engineered peptide...
February 6, 2017: Chemical Biology & Drug Design
Adriane F Brito, James O Fajemiroye, Hiasmin F S Neri, Dayane M Silva, Daiany P B Silva, Germán Sanz, Boniek G Vaz, Flávio S de Carvalho, Paulo C Ghedini, Luciano M Lião, Ricardo Menegatti, Elson A Costa
In this study we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening refered to as Irwin test, prior to sodium pentobarbital-induced sleep, open field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test...
February 3, 2017: Chemical Biology & Drug Design
Albert H Chan, Sung Wook Yi, Ethan M Weiner, Brendan R Amer, Christopher K Sue, Jeff Wereszczynski, Carly A Dillen, Silvia Senese, Jorge Z Torres, J Andrew McCammon, Lloyd S Miller, Michael E Jung, Robert T Clubb
Staphylococcus aureus is a leading cause of hospital-acquired infections in the United States and is a major health concern as methicillin-resistant S. aureus (MRSA) and other antibiotic resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches...
February 3, 2017: Chemical Biology & Drug Design
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