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Xiaoze Bao, Shiqiang Wei, Xingkai Qian, Jingping Qu, Baomin Wang, Liwei Zou, Guangbo Ge
A catalytic asymmetric [3 + 2] cyclization of novel 4-isothiocyanato pyrazolones and isatin-derived ketimines was developed, delivering a wide range of intriguing dispirotriheterocyclic products in high yield with excellent diastereoselectivity and enantioselectivity. A chiral sulfoxide derivative of this dispirocyclic product was identified to be a promising hit of the human carboxylesterase 1 inhibitor, and the significant difference of the activity between two enantiomers emphasized the importance of this asymmetric process...
May 22, 2018: Organic Letters
Sana Farooq Ahmad, Ibrar Khan, Abdul Wadood, Sadiq Azam, Noor Rehman, Muhammad Waqas, Kashif Bashir, Asaf Ali Khan
Hospitals are the most prominent places for the growth and spread of bacteria which are resistant to the available antibiotics. This antibiotic resistance is due to the over and misuse of antibiotic dosages of a high-density of patient population which are in frequent interaction with inanimate items of the hospitals and the consequent risk of cross infection. Out of 1010 samples of the current study, 510 (50.49%) were culture positive of which 329 (64.5%) were Gram-positive while 181 (35.49%) Gram negative...
April 22, 2018: Computational Biology and Chemistry
Samuel J S Rubin, Yftah Tal-Gan, Chaim Gilon, Nir Qvit
Protein-protein interactions (PPIs) are particularly important for controlling both physiologic and pathologic biological processes but are difficult to target due to their large and/or shallow interaction surfaces unsuitable for small molecules. Linear peptides found in nature interact with some PPIs, and protein active regions can be used to design synthetic peptide compounds for inhibition of PPIs. However, linear peptides are limited therapeutically by poor metabolic and conformational stability, which can compromise their bioactivity and half-life...
May 17, 2018: Current Topics in Medicinal Chemistry
Till Wüstemann, Uwe Haberkorn, John Babich, Walter Mier
The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate-specific membrane antigen (PSMA), a membrane-bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor-associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules...
May 17, 2018: Medicinal Research Reviews
Steven J Smith, Xue Zhi Zhao, Terrence R Burke, Stephen H Hughes
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates...
May 16, 2018: Retrovirology
Bassam M Ayoub, Yasmeen M Attia, Mahmoud S Ahmed
Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Rucha R Wani, Hemchandra K Chaudhari
Docking and 3D QSAR studies were performed on Inhibitor of Bacterial DNA gyrase to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in PHASE; with a diverse set of 58 bacterial DNA gyrase inhibitors. A five point CPH with H-bond acceptor(A), Hydrophobic (H), Hydrogen bond Donor(D), Aromatic ring(R), a basic or positively ionizable feature. From them, the best pharmacophore hypothesis AAAPR gives a statistically significant and 3D QSAR model with 0.92 as R-squared value and 0...
May 15, 2018: Current Computer-aided Drug Design
Nivedita S Mahajani, John D Chisholm
1,1'-Diarylbutyl groups are a common pharmacophore found in many biologically active small molecules. To access these systems under mild conditions, the reaction of diarylmethyl trichloroacetimidates with allyltributylstannanes was explored. Simply heating allyltributylstannane with the trichloroacetimidate resulted in substitution of the imidate with an allyl group. Unlike other methods used to access these systems, no strong base, transition metal catalyst, Brønsted acid or Lewis acid promoter was required to affect the transformation...
May 16, 2018: Organic & Biomolecular Chemistry
Ramakrishna Nirogi, Abdul Rasheed Mohammed, Anil K Shinde, Shankar Reddy Gagginapally, Durga Malleshwari Kancharla, Vanaja Reddy Middekadi, Narsimha Bogaraju, Srinivasa Rao Ravella, Pooja Singh, Sumit Raosaheb Birangal, Ramkumar Subramanian, Raghava Choudary Palacharla, Vijay Benade, Nageswararao Muddana, Pradeep Jayarajan
Alzheimer's disease (AD) is a neurodegenerative disorder which has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. The 5-HT4 receptor (5-HT4R) partial agonists offer both symptomatic and disease modifying treatment as they shift amyloid precursor protein (APP) processing from amyloidogenic to non-amyloidogenic pathway by activating α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing neurotransmitter acetylcholine levels in the brain...
May 15, 2018: Journal of Medicinal Chemistry
Pankaj Kumar Singh, Om Silakari
Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases...
April 25, 2018: Bioorganic Chemistry
Burak Tuzun, Sevtap Caglar Yavuz, Nazmiye Sabanci, Emin Saripinar
In the present work, pharmacophore identification and biological activity prediction for 86 pyrazole pyridine carboxylic acid derivatives were made using the electron conformational genetic algorithm approach which was introduced as a 4D-QSAR analysis by us in recent years. In the light of the data obtained from quantum chemical calculations at HF/6-311 G** level, the electron conformational matrices of congruity (ECMC) were constructed by EMRE software. Comparing the matrices, electron conformational submatrix of activity (ECSA, Pha) was revealed that are common for these compounds within a minimum tolerance...
May 13, 2018: Current Computer-aided Drug Design
Yahya Guzel, Ertugrul Aslan, Burcin Turkmenoglu, E Mesut Su
In this paper, we have introduced a new atomic descriptor with Klopman index to determine the local reactive sites of the molecular systems during electrophilic, nucleophilic attacks. This index, similar to other local reactivity descriptors but more advanced, has been used as a realistic descriptor to discover new aspects of molecular structure. Nonlinear least squares (NLLS) methods to define the parameters maximizing the fit between the observed points and the computed simulation results were performed according to the Levenberg-Marquardt (LM) algorithm...
May 13, 2018: Current Computer-aided Drug Design
Madhu Sudhana Saddala, Pradeepkiran Jangampalli Adi
Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies...
May 2018: Heliyon
Mohammad Ali Ahmaditaba, Mohammad Hassan Houshdar Tehrani, Afshin Zarghi, Sorayya Shahosseini, Bahram Daraei
A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2 Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e. , compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0...
2018: Iranian Journal of Pharmaceutical Research: IJPR
Shivangi Agarwal, Ekta Verma, Vivek Kumar, Namrita Lall, Samaresh Sau, Arun K Iyer, Sushil K Kashaw
Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB...
May 3, 2018: Journal of Molecular Graphics & Modelling
Genyan Liu, Wenjie Wang, Youlan Wan, Xiulian Ju, Shuangxi Gu
Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0...
May 11, 2018: International Journal of Molecular Sciences
Youjun Xu, Shiwei Wang, Qiwan Hu, Shuaishi Gao, Xiaomin Ma, Weilin Zhang, Yihang Shen, Fangjin Chen, Luhua Lai, Jianfeng Pei
CavityPlus is a web server that offers protein cavity detection and various functional analyses. Using protein three-dimensional structural information as the input, CavityPlus applies CAVITY to detect potential binding sites on the surface of a given protein structure and rank them based on ligandability and druggability scores. These potential binding sites can be further analysed using three submodules, CavPharmer, CorrSite, and CovCys. CavPharmer uses a receptor-based pharmacophore modelling program, Pocket, to automatically extract pharmacophore features within cavities...
May 10, 2018: Nucleic Acids Research
Mohd Imran Ansari, Mohd M Khan, Mohammad Saquib, Shahnaaz Khatoon, Mohd Kamil Hussain
Dithiolethiones are five-membered sulfur-containing cyclic scaffolds that exhibit antioxidative, anti-inflammatory, antithrombic and chemotherapeutic activities. Dithiolethiones display the chemopreventive and cytoprotective effects by activating the antioxidant response element and mounting the transcription of cytoprotective phase II enzymatic machinery. In addition, several classes of dithiolethiones efficiently modulate the activities of proteins that play crucial roles in normal and cancer cells, including glutathione S-transferase, cyclooxygenases and master regulator NF-κB...
May 11, 2018: Future Medicinal Chemistry
Duraippandi Palanimuthu, Zhixuan Wu, Patric J Jansson, Nady Braidy, Paul V Bernhardt, Des R Richardson, Danuta S Kalinowski
Alzheimer's disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of CuII-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation...
May 11, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Xie-Huang Sheng, Cheng-Cheng Cui, Chao Shan, Yu-Zhen Li, Duo-Hong Sheng, Bin Sun, De-Zhan Chen
Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides. It has drawn considerable attention owing to its putative involvement in diverse neurodegenerative diseases. Ferrostatins are the first identified inhibitors of ferroptosis and they inhibit ferroptosis by efficiently scavenging free radicals in lipid bilayers. However, their further medicinal application has been limited due to the deficient knowledge of the lipid peroxyl radical-trapping mechanism...
May 11, 2018: Organic & Biomolecular Chemistry
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