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Chemical Biology & Drug Design

Shiyang Zhou, Guangying Chen, Gangliang Huang
The Albendazole was used as the lead compound, which was modified by structural transformation and with alkyl groups. A total of 18 compounds(4a-4r) were designed and synthesized.The in vitro experiment results showed thatcompounds 4e, 4f, 4k, 4l, 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC50 of compound 4l to anti-egg of roundworm was 0.65±0.01 μmol/L and to anti-imago of roundworm was 1.04±0.01 μmol/L. At the same time, it showed thatcompound 4l had the best effect in vivo, and the rate of anti-helmintic could reach more than 99%...
November 14, 2018: Chemical Biology & Drug Design
Agnieszka Zagórska, Anna Partyka, Adam Bucki, Marcin Kołaczkowski, Magdalena Jastrzębska-Więsek, Anna Czopek, Agata Siwek, Monika Głuch-Lutwin, Marek Bednarski, Marek Bajda, Jakub Jończyk, Kamil Piska, Paulina Koczurkiewicz, Anna Wesołowska, Maciej Pawłowski
A series of 2-pyrimidynyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor...
November 13, 2018: Chemical Biology & Drug Design
Joyce K Daré, Teodorico C Ramalho, Matheus P Freitas
Quantitative Structure-Activity Relationship (QSAR) is a molecular modeling technique widely used in the discovery of novel drugs. Currently, there are many approaches for performing such analysis, which are commonly classified from 1D-6D. 2D and 3D techniques are amongst the most exploited ones. Multivariate Image Analysis applied to QSAR (MIA-QSAR) is an example of 2D methodology that has presented a satisfactory performance in the generation of effective prediction models for biological/physicochemical properties...
November 9, 2018: Chemical Biology & Drug Design
Arshad Mehmood, Muhammad Ishaq, Lei Zhao, Bushra Safdar, Ashfaq-Ur Rehman, Masooma Munir, Ali Raza, Muhammad Nadeem, Waheed Iqbal, Chengtao Wang
Hyperuricemia (HUA), a disease due to an elevation of BUA (body uric acid) level and responsible for various diseases like gout, cardiovascular disorders, and renal failure, is a major ground debate for the medical science these days. Considering the risk factors linked with allopathic drugs for the treatment of this disease, the debate has now become a special issue. Previously, we critically discussed the role of dietary polyphenols in the treatment of HUA. Besides dietary food plants, many researchers figure out the tremendous effects of medicinal plants derived phytochemicals against HUA...
November 7, 2018: Chemical Biology & Drug Design
Wei Hou, Guanjun Zhang, Zhi Luo, Lin Su, Hongtao Xu
A series of novel 4α-triazole acetate podophyllotoxin derivatives were synthesized via click-chemistry. In vitro cytotoxic activity evaluation showed that most of the derivatives exhibited potent inhibitory activities against the tested cancer cell lines with low nanomolar IC50 values. Further studies demonstrated that compound 31 exhibited broad-spectrum cytotoxic activities, effectively overcame drug-resistance and showed relatively weak cytotoxicity on non-cancer cells. Preliminary mechanistic studies indicated that 31 might have action on microtubule, cause cell cycle arrest at G2/M phase and induce apoptosis in human PC-3 cancer cells...
November 4, 2018: Chemical Biology & Drug Design
Mallu Lavanya, Indira Viswambaran Asharani, Dhakshanamurthy Thirumalai
A new series of functionalized fused pyridines 4(a-i) and fused pyrido[2,3-d]pyrimidines 8(a-c) were designed and synthesized through a multi component reaction where in pyridine ring formation step plays a key role. All the newly formed compounds were well characterized by spectral techniques such as FTIR, 1 HNMR, 13 CNMR, HRMS and XRD. The potential therapeutic activities such as anti-inflammatory activity by protein denaturation and RBC membrane stabilization methods, and anti-oxidant activity by DPPH scavenging method of the newly synthesized compounds were studied...
November 4, 2018: Chemical Biology & Drug Design
Amany S Mostafa, Rania M Gomaa, Mohammad A Elmorsy
Three new series of 2-phenyl benzimidazole-based derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity against breast cancer (MCF-7) cell lines. Three compounds 8, 9 and 15 showed high cytotoxic activities, with IC50 values of 3.37, 6.30 and 5.84 μM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including non tumorigenic breast epithelial cell line (MCF-10F), skin fibroblast cell line (BJ) and lung fibroblast cell line (MRC-5)...
November 4, 2018: Chemical Biology & Drug Design
Angamba Meetei Potshangbam, Raja Polavarapu, R S Rathore, Naresh Damuka, N Prakash Prabhu, Nongdam Potshangbam, Pravind Kumar, Vaibhav Vindal
Natural products have been the source of treatment for various human diseases from time immemorial. Interests in natural product based scaffolds for the discovery of modern drugs has grown in recent years. However, research on exploring the traditional medicinal systems for modern therapeutics is severely limited due to our incomplete understanding of therapeutic mechanism of action. One possible solution is to develop computational approaches, based on ligand- and structure-based screening tools, for fast and plausible target identification, leading to elucidation of therapeutic mechanism...
October 31, 2018: Chemical Biology & Drug Design
Ivan Pires de Oliveira, Caroline Honaiser Lescano, Gilberto De Nucci
Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the hydrolysis of cyclic guanosine monofosfate (cGMP) to guanosine monophosphate (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells with various biological and therapeutic effects. Several PDE-5 inhibitors exist, with tadalafil being one of the most commonly studied and used in clinical therapy. In this study, we applied Molecular Dynamics (MD) simulations coupled to the ABF (Adaptive Biasing Force) method to study the effect of the mutation on the Gln817 residue (Q817G)...
October 31, 2018: Chemical Biology & Drug Design
Ziye Liu, Fan Jiang, Yun-Dong Wu
Aβ42 peptide, with two additional residues at C-terminus, aggregates much faster than Aβ40. We performed equilibrium replica exchange molecular dynamics simulations of their monomers using our residue-specific force field. Simulated 3 JHNH α -coupling constants agree excellently with experimental data. Aβ40 and Aβ42 have very similar local conformational features, with considerable β-strand structures in the segments: A2-H6 (A), L17-A21 (B), A30-V36 (C) of both peptides and V39-I41 (D) of Aβ42. Both peptides have abundant A-B and B-C contacts, but Aβ40 has much more contacts between A and C than Aβ42, which may retard its aggregation...
October 31, 2018: Chemical Biology & Drug Design
Yiqiu Zhang, Lanfang Meng, Beilei Li, Hui Tan, Qing-Yu Lin, Dengfeng Cheng, Hongcheng Shi
A novel 99m Tc-tricine-EDDA-Hynic-c-Met molecular probe was synthetized, and nude mice models of human non-small-cell lung cancer (NSCLC) were established in order to preliminarily investigate that whether the molecular probe can be used to screen c-Met inhibitor for targeted drug therapy in NSCLC METHODS: With Hynic as the chelating agent, 99m TcO4 -labeled c-Met receptor was used to synthetize 99m Tc-tricine-EDDA-Hynic-c-Met. Two nude mice successfully transplanted with H1993 tumor and two nude transplanted with H292 tumor were injected with 99m Tc-tricine-EDDA-Hynic-c-Met through the tail vein...
October 31, 2018: Chemical Biology & Drug Design
Xiuyan Yang, Meng Deng, Xi Zhang, Kun Song, Cong Ruan, Linghua Meng, Jian Zhang
A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mTOR pathway...
October 31, 2018: Chemical Biology & Drug Design
Dongwei Kang, Zhao Wang, Meng Chen, Da Feng, Gaochan Wu, Zhongxia Zhou, Lanlan Jing, Xiaofang Zuo, Xiangyi Jiang, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Two novel series of human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2-d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated with active potency against wild-type (WT) HIV-1 strain in MT-4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1. Compound 7 (EC50 = 0...
October 31, 2018: Chemical Biology & Drug Design
Syed Faheem Askari Rizvi, Saleha Tariq, Muhammad Mehdi, Ahmad Junaid Hassan
Roxithromycin is a second-generation macrolide antibiotic derived from erythromycin. In the current study, roxithromycin (ROX) was successfully labeled with technetium-99m for early diagnosis of bacterial infection and discrimination between septic and aseptic inflammation. The highest radiochemical purity of ≥95% was achieved by investigating different labeling parameters such as pH, ligand/reducing agent concentration, temperature, and amount of stabilizing agent. For this purpose, 0.3-0.5 mg ligand, 2-6 μg SnCl2 ·2H2 O as a reducing agent at basic pH (8-10 pH) and 2 mg mannitol used as a stabilizing agent, in the end, 370 MBq 99m Tc added into the reaction vials and incubated for a wide range of temperature (-4 to 65°C)...
October 29, 2018: Chemical Biology & Drug Design
Ajmer Singh Grewal, Rajeev Kharb, Deo Nandan Prasad, Jagdeep Singh Dua, Viney Lather
Glucokinase (GK) is the key enzyme controlling levels of blood glucose under normal physiological range and GK activators are emerging class of drug candidates with promising hypoglycaemic activity. The current study was planned to design, synthesize and evaluate novel N-pyridin-2-yl benzamide analogues as allosteric activators of GK. A novel series of N-pyridin-2-yl benzamide analogues were synthesized starting from 3-nitrobenzoic acid and evaluated in vitro for GK activation followed by in silico studies to predict the binding interactions of the designed molecules with GK protein...
October 28, 2018: Chemical Biology & Drug Design
Gleicekelly Silva Coelho, Josimara Souza Andrade, Viviane Flores Xavier, Policarpo Ademar Sales, Barbara Caroline Rodrigues de Araujo, Kátia da Silva Fonseca, Melissa Soares Caetano, Silvane Maria Fonseca Murta, Paula Melo de Abreu Vieira, Claudia Martins Carneiro, Jason Guy Taylor
Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease are still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters...
October 25, 2018: Chemical Biology & Drug Design
Abdul Mannan Baig, R Zohaib, W Nuzair, K Saiqa, N Mehdia
We for the first time report the primitive origins of eukaryotic voltage-gated calcium channels [Cav] in the eukaryotic time-line. The evolution of Cav in eukaryotes is an area of interest for biologists worldwide. The CLAN CL0030 and its family Ion_Trans 2 PF 07885 has been known to be present in prokaryotes, but the origin of these channels in Acanthamoeba are yet to be determined. We inferred the origin of primitive forms of two pore channels [TPC] like proteins, human-like Cav 1.1 of L type and Cav subunit alpha-2/delta in Acanthamoeba spp early during evolution...
October 25, 2018: Chemical Biology & Drug Design
Ozildéia S Trefzger, Amarith R das Neves, Natália V Barbosa, Diego B Carvalho, Indiara C Pereira, Renata T Perdomo, Maria F C Matos, Nidia C Yoshida, Massuo J Kato, Sérgio de Albuquerque, Carla C P Arruda, Adriano C M Baroni
Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G, were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43-90%. Anti-trypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L...
October 24, 2018: Chemical Biology & Drug Design
Noreen Akhtar, Ishrat Jabeen, Nasir Jalal, Jon Antilla
Protein Kinase B-beta (PKBβ/Akt2) is a non-receptor kinase that has attracted a great deal of attention as a promising cancer therapy drug target. In mammalian cells, hyper-activation of Akt2 exclusively facilitates the survival of solid tumors by interfering with cell cycle progression. This definite function of Akt2 in tumor survival/maintenance provides the basis for the development of its antagonists with the aim of desensitizing cell proliferation. In order to find novel and potent Akt2 inhibitors, structure-based pharmacophore models have been developed and validated by the test set prediction...
October 24, 2018: Chemical Biology & Drug Design
Joydip Das
Defining molecular targets of alcohol and understanding the molecular mechanism of alcohol actions are necessary to develop effective therapeutics for alcohol use disorder (AUD). Here, we describe a detailed protocol for identifying alcohol-binding site(s) in proteins using diazirine-based azialcohol as photoaffinity labeling agents. Upon photoirradiation, azialcohol photoincorporates into alcohol-binding proteins. The stoichiometry and site of azialcohol photoincorporation can be determined using high-resolution mass spectrometry...
October 22, 2018: Chemical Biology & Drug Design
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