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Future Medicinal Chemistry

Eva Ramos, Alejandro Romero, Javier Egea, José Marco-Contelles, Javier Del Pino, Cristóbal de Los Ríos
AIM: The 1,8-naphthyridine CR80 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate) has shown interesting neuroprotective properties in in vitro and in vivo models of neurodegeneration. In spite of these promising outcomes, the molecular and cellular mechanisms underlying CR80 actions need to be further explored. MATERIALS & METHODS: We herein report the signal transduction pathways involved in developmental, neuroprotective and stress-activated processes, as well as the gene expression regulation by CR80 in SH-SY5Y neuroblastoma cells...
March 21, 2018: Future Medicinal Chemistry
Modi Wang, Moloud A Sooreshjani, Clinton Mikek, Clement Opoku-Temeng, Herman O Sintim
AIM: Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-based medium throughput screening for inhibitors of cGAS identified suramin as a potent inhibitor. Unlike other reported cGAS inhibitors, which bind to the ATP/GTP binding site, suramin displaced the bound DNA from cGAS. Addition of suramin to THP1 cells reduced the levels of IFN-β mRNA and protein...
March 21, 2018: Future Medicinal Chemistry
Claudiu T Supuran
Mammalian carbonic anhydrases (CAs; EC of which 16 isoforms are known, are involved in important physiological functions. Their inhibition is exploited pharmacologically for the treatment of many diseases (glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, etc.) but the activators were less investigated till recently. A review on the CA activation is presented, with the activation mechanism, drug design approaches of activators and comparison of the various isoforms activation profiles being discussed...
February 26, 2018: Future Medicinal Chemistry
Arcadia Woods, Khondaker Miraz Rahman
Inhaled antimicrobials have been extremely beneficial in treating respiratory infections, particularly chronic infections in a lung with cystic fibrosis. The pulmonary delivery of antibiotics has been demonstrated to improve treatment efficacy, reduce systemic side effects and, critically, reduce drug exposure to commensal bacteria compared with systemic administration, reducing selective pressure for antimicrobial resistance. This review will explore the specific challenges of pulmonary delivery of a number of differing antimicrobial molecules, and the formulation and technological approaches that have been used to overcome these difficulties...
February 23, 2018: Future Medicinal Chemistry
Andrés González, María F Fillat, Ángel Lanas
Antibiotics have saved millions of lives over the past decades. However, the accumulation of so many antibiotic resistance genes by some clinically relevant pathogens has begun to lead to untreatable infections worldwide. The current antibiotic resistance crisis will require greater efforts by governments and the scientific community to increase the research and development of new antibacterial drugs with new mechanisms of action. A major challenge is the identification of novel microbial targets, essential for in vivo growth or pathogenicity, whose inhibitors can overcome the currently circulating resistome of human pathogens...
February 20, 2018: Future Medicinal Chemistry
Dina Manetti, Cristina Bellucci, Niccolò Chiaramonte, Silvia Dei, Elisabetta Teodori, Maria Novella Romanelli
Nicotinic receptors are membrane proteins involved in several physiological processes. They are considered suitable drug targets for various CNS disorders or conditions, as shown by the large number of compounds which have entered clinical trials. In recent years, nonconventional agonists have been discovered: positive allosteric modulators, allosteric agonists, site-specific agonists and silent desensitizers are compounds able to modulate the receptor interacting at sites different from the orthodox one, or to desensitize the receptor without prior opening...
February 16, 2018: Future Medicinal Chemistry
Neetu Dayal, Clement Opoku-Temeng, Delmis E Hernandez, Moloud Aflaki Sooreshjani, Brandon A Carter-Cooper, Rena G Lapidus, Herman O Sintim
AIM: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. RESULTS: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines...
February 13, 2018: Future Medicinal Chemistry
Xiaoda Yang
No abstract text is available yet for this article.
February 13, 2018: Future Medicinal Chemistry
Can Liu, Longhai Dai, Yueping Liu, Dequan Dou, Yuanxia Sun, Lanqing Ma
No abstract text is available yet for this article.
February 12, 2018: Future Medicinal Chemistry
Heba A Ibrahim, Fadi M Awadallah, Hanan M Refaat, Kamilia M Amin
AIM: Computer-aided drug design techniques were adopted to design three series of 2-substituted-5-nitrobenzimidazole derivatives hybridized with piperzine 5a,b, oxadiazole 7a,b, 9, 14a-c and triazolo-thiadiazole moieties 12a-d, as VEGFR-2/c-Met kinase inhibitors. MATERIALS & METHODS: The designed compounds were synthesized adopting the chemical pathways outlined in schemes 1 and 2 to afford the desired three series followed by evaluating their inhibitory activities against VEGFR-2 and c-Met and in vitro anticancer activities...
February 12, 2018: Future Medicinal Chemistry
Wanderson A da Silva, Luiz Crp da Silva, Vinicius R Campos, Maria Cbv de Souza, Vitor F Ferreira, Ângela Cpb Dos Santos, Plínio C Sathler, Gabriella S de Almeida, Flaviana Rf Dias, Lucio M Cabral, Rodrigo Bv de Azeredo, Anna C Cunha
AIM: Cancer has emerged as a growing public health problem in many parts of the world. METHODOLOGY: We describe the synthesis of a series of carbohydrate-based isoquinoline-5,8-diones through the 1,4-addition reaction between 5,8-dioxo-5,8-dihydroisoquinoline and aminocarbohydrates. Halogenated quinones were also synthesized. Their inhibitory effects on the proliferation of human cancer cell lines were studied. RESULTS & CONCLUSION: The most promising compound, derived from isoquinoline-5,8-dione, containing ribofuranosidyl ring, was selectively active in vitro against H1299 cancer cells, with 1...
February 9, 2018: Future Medicinal Chemistry
Barbara Bednarczyk-Cwynar, Piotr Ruszkowski, Tomasz Jarosz, Katarzyna Krukiewicz
AIM: Triterpenes are natural compounds, whose wide biological activity predestines them for application as promising new chemotherapeutics. In this paper, we report the results of our investigations into the substitution of oleanolic acid with aromatic and nitroaromatic moieties acting as bioreducing agents. RESULTS: The process of reduction of nitro groups was investigated through cyclic voltammetry, UV-Vis and electron paramagnetic resonance spectroelectrochemistry...
February 9, 2018: Future Medicinal Chemistry
Jan Pokorny, Sona Krajcovicova, Marian Hajduch, Martin Holoubek, Sona Gurska, Petr Dzubak, Tereza Volna, Igor Popa, Milan Urban
AIM: From betulinic acid (1a), we synthesized 30-oxobetulinic acid (2a) that is highly cytotoxic against many cancer cell lines; however, its generic toxicity is the main obstacle in further development as cytostatic. Methodology & results: From 2a, we prepared a new class of compounds - nonsymmetrical azines and tested their in vitro cytotoxicity. All new azines with a free 28-COOH group (4a-4e) were highly and selectively cytotoxic against the T-lymphoblastic leukemia cell line CCRF-CEM and exhibited dose-dependent inhibition of RNA and DNA synthesis and other cell-cycle alterations, including the M-phase block...
February 9, 2018: Future Medicinal Chemistry
Supojjanee Sansook, Wei Tuo, Mélanie Bollier, Amélie Barczyk, Xavier Dezitter, Fredérique Klupsch, Natascha Leleu-Chavain, Amaury Farce, Graham J Tizzard, Simon J Coles, John Spencer, Régis Millet
Ferrocene analogs of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bio-organometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on fatty acid amide hydrolase. None had any fatty acid amide hydrolase activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole-3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM).
February 8, 2018: Future Medicinal Chemistry
Valentina Oliveri, Graziella Vecchio
This review focuses on metal complexes of cyclodextrin (CyD) derivatives designed for application as therapeutics or diagnostics. We discuss examples of metalloprotein models (hemoglobin, superoxide dismutase and catalase) based on cyclodextrins. The hydrophobic microenvironment of CyDs stabilizes the Fe(II) porphyrin system that can reversibly bind O2 or CO in water. Superoxide dismutase/catalase mimetics exploit functionalization with CyDs, which increase their solubility and biological activity. Furthermore, CyDs have been used as scaffolds to obtain multicenter metal complexes: paramagnetic systems act as high-performance contrast agents for magnetic resonance imaging applications...
February 8, 2018: Future Medicinal Chemistry
Ryo Masuda, Risa Hayashi, Hiroshi Nose, Akihiro Taguchi, Yoshio Hayashi, Hiroyuki Yasui, Takaki Koide
AIM: The development of a platinum anticancer agent that has improved efficacy by efficient delivery to a tumor and that suppresses side effects has been investigated. Arginine-rich triple-helical peptides are promising drug carriers because of their stability in body fluids and cell-penetrating activity. RESULTS: We synthesized a carboplatin derivative conjugated with an arginine-rich triple-helical peptide. This derivative released platinum under acidic conditions or in the presence Cl- ions...
February 7, 2018: Future Medicinal Chemistry
Hee-Kyung Kim, Gang Ho Lee, Yongmin Chang
MRI contrast is often enhanced using a contrast agent. Gd3+-complexes are the most widely used metallic MRI agents, and several types of Gd3+-based contrast agents (GBCAs) have been developed. Furthermore, recent advances in MRI technology have, in part, been driven by the development of new GBCAs. However, when designing new functional GBCAs in a small molecular-weight or nanoparticle form for possible clinical applications, their functions are often compromised by poor pharmacokinetics and possible toxicity...
February 7, 2018: Future Medicinal Chemistry
Niels Geudens, Davy Sinnaeve, José C Martins
No abstract text is available yet for this article.
February 7, 2018: Future Medicinal Chemistry
Muhammad Hanif, Christian G Hartinger
Despite the severe side effects and the emergence of drug resistance, the use of DNA-targeting platinum drugs remains strong either alone or in a combination chemotherapy regimen. New strategies and formulations are being explored in the design of anticancer metal complexes that exhibit nonclassical modes of action, selectively hit precise biomolecular targets or are even able to induce immunogenic anticancer activity. These developments will ameliorate the systemic toxicity of metal-based drugs and widen the range of treatable cancers...
February 7, 2018: Future Medicinal Chemistry
Hao Liu, Yunwei Qu, Xiaohui Wang
Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder that affects millions of people around the world. The aggregation of amyloid-β peptides (Aβ), one of the primary pathological hallmarks of AD, plays a key role in the AD pathogenesis. In this regard, Aβ aggregates have been considered as both biomarkers and drug targets for the diagnosis and therapy of AD. Various Aβ-targeted metal complexes have exhibited promising potential as anti-AD agents due to their fascinating physicochemical properties over the past two decades...
February 5, 2018: Future Medicinal Chemistry
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