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Future Medicinal Chemistry

Ling Tang, Zhuchun Bei, Yabin Song, Likun Xu, Hong Wang, Dongna Zhang, Yuanyuan Dou, Kai Lv, Hongquan Wang
AIM: Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used. METHODOLOGY: We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice...
May 17, 2017: Future Medicinal Chemistry
Ivani Pauli, Leonardo G Ferreira, Mariana L de Souza, Glaucius Oliva, Rafaela S Ferreira, Marco A Dessoy, Brian W Slafer, Luiz C Dias, Adriano D Andricopulo
AIM: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. METHODOLOGY: Chemometric analyses were performed on the data set using the HQSAR, CoMFA and CoMSIA methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D QSAR models and to assess the inhibitor binding modes and intermolecular interactions...
May 16, 2017: Future Medicinal Chemistry
Julien Lalut, Delphine Karila, Patrick Dallemagne, Christophe Rochais
Alzheimer's disease (AD) is the most common form of dementia affecting millions of patients worldwide which can only be treated with symptomatic drugs. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of 5-HT6R and 5-HT4R appeared to be promising. This modulation has been proved to enhance the cognition in AD through modulation of the neurotransmitter system but could also be beneficial in order to limit the amyloid pathology...
May 15, 2017: Future Medicinal Chemistry
Kenneth Lundstrom
No abstract text is available yet for this article.
May 15, 2017: Future Medicinal Chemistry
Maria Laura Bolognesi
No abstract text is available yet for this article.
May 15, 2017: Future Medicinal Chemistry
Youssef Dgachi, Helène Martin, Alexandre Bonet, Mourad Chioua, Isabel Iriepa, Ignacio Moraleda, Fakher Chabchoub, José Marco-Contelles, Lhassane Ismaili
AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. RESULTS: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity...
May 15, 2017: Future Medicinal Chemistry
Ross P McGeary, Daniel Tc Tan, Gerhard Schenk
The global overuse of antibiotics has led to the emergence of drug-resistant pathogenic bacteria. Bacteria can combat β-lactams by expressing β-lactamases. Inhibitors of one class of β-lactamase, the serine-β-lactamases, are used clinically to prevent degradation of β-lactam antibiotics. However, a second class of β-lactamase, the metallo-β-lactamases (MBLs), function by a different mechanism to serine-β-lactamases and no inhibitors of MBLs have progressed to be used in the clinic. Bacteria that express MBLs are an increasingly important threat to human health...
May 15, 2017: Future Medicinal Chemistry
Damijan Knez, Matej Sova, Urban Košak, Stanislav Gobec
Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field...
May 15, 2017: Future Medicinal Chemistry
Haixing Guan, Yongli Du, Yang Ning, Xin Cao
The EGFR is one of the most popular targets for anticancer therapies and many drugs, such as erlotinib and gefitinib, have got enormous success in clinical treatments of cancer in past decade. However, the efficacy of these agents is often limited because of the quick emergence of drug resistance. Fundamental structure researches of EGFR in recent years have generally elucidated the mechanism of drug resistance. In this review, based on systematic resolution of full structures of EGFR and their variants via single crystal x-ray crystallography, the working and drug resistance mechanism of EGFR-targeted drugs are fully illustrated...
May 15, 2017: Future Medicinal Chemistry
Angela Rampa, Serena Montanari, Letizia Pruccoli, Manuela Bartolini, Federico Falchi, Alessandra Feoli, Andrea Cavalli, Federica Belluti, Silvia Gobbi, Andrea Tarozzi, Alessandra Bisi
AIM: Alzheimer's disease is a still untreatable multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this picture, the recent reformulation of the cholinergic hypothesis renewed the interest for acetylcholinesterase inhibitors. In this paper, a series of naturally inspired chalcone-based carbamates was designed to target cholinesterase enzymes and possibly generate fragments endowed with neuroprotective activity in situ. Results & methodology: All compounds presented in this study showed nanomolar potency for cholinesterase inhibition...
May 12, 2017: Future Medicinal Chemistry
Eva Ramos, Javier Egea, Cristóbal de Los Ríos, José Marco-Contelles, Alejandro Romero
Melatonin is an indoleamine produced mainly in the pineal gland. The natural decline of melatonin levels with aging strongly contributes to the development of neurodegenerative disorders. Pleiotropic actions displayed by melatonin prevent several processes involved in neurodegeneration such as neuroinflammation, oxidative stress, excitotoxicity and/or apoptosis. This review focuses on a number of melatonin hybrids resulting from the juxtaposition of tacrine, berberine, tamoxifen, curcumin, N,N-dibenzyl(N-methyl)amine, among others, with potential therapeutic effects for the treatment of neurodegenerative diseases...
May 12, 2017: Future Medicinal Chemistry
Elizabeth Larocque, N Naganna, Xiaochu Ma, Clement Opoku-Temeng, Brandon Carter-Cooper, Gaurav Chopra, Rena G Lapidus, Herman O Sintim
AIM: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism. RESULTS: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835...
May 11, 2017: Future Medicinal Chemistry
Baldur Sveinbjørnsson, Ketil Andre Camilio, Bengt Erik Haug, Øystein Rekdal
The oncolytic peptide LTX-315, which has been de novo designed based on structure-activity relationship studies of host defense peptides, has the ability to kill human cancer cells and induce specific anticancer immune response when injected locally into tumors established in immunocompetent mice. The oncolytic effect of LTX-315 involves perturbation of plasma membrane and the mitochondria with subsequent release of danger-associated molecular pattern molecules, which highlights the ability of LTX-315 to induce complete regression and protective immune responses...
May 11, 2017: Future Medicinal Chemistry
Ana M García, Irene G Salado, Daniel I Perez, José Brea, Jose A Morales-García, Alejandro González-García, María Isabel Cadavid, María Isabel Loza, Francisco Javier Luque, Ana Perez-Castillo, Ana Martinez, Carmen Gil
AIM: Since neuroinflammation is partially mediated by cAMP levels and PDE10A enzyme is able to regulate these levels being highly expressed in striatum, its inhibitors emerged as useful drugs to mitigate this inflammatory process and hence the neuronal death associated with Parkinson's disease (PD). Methodology & results: To study the utility of PDE10A as a pharmacological target for PD, in this work we propose the search and development of new PDE10A inhibitors that could be useful as pharmacological tools in models of the disease and presumably as potential drug candidates...
May 9, 2017: Future Medicinal Chemistry
Pui Shing Ho
No abstract text is available yet for this article.
May 9, 2017: Future Medicinal Chemistry
Houssem Boulebd, Lhassane Ismaili, Helene Martin, Alexandre Bonet, Mourad Chioua, José Marco Contelles, Ali Belfaitah
AIM: Due to the multifactorial nature of Alzheimer's disease, there is an urgent search for new more efficient, multitarget-directed drugs. RESULTS: This paper describes the synthesis, antioxidant and in vitro biological evaluation of ten (benz)imidazopyridino tacrines (7-16), showing less toxicity than tacrine at high doses, and potent cholinesterase inhibitory capacity, in the low micromolar range. Among them, compound 10 is a nonhepatotoxic tacrine at 1000 mM, showing moderate, but totally selective electric eel acetylcholinesterase inhibition, whereas molecule 16 is twofold less toxic than tacrine at 1000 μM, showing moderate and almost equipotent inhibition for electric eel acetylcholinesterase and equine butyrylcholinesterase...
May 9, 2017: Future Medicinal Chemistry
Jürgen Bajorath
No abstract text is available yet for this article.
May 9, 2017: Future Medicinal Chemistry
Sandra Gunesch, Simon Schramm, Michael Decker
No abstract text is available yet for this article.
May 9, 2017: Future Medicinal Chemistry
Sayanti Brahmachari, Ashim Paul, Daniel Segal, Ehud Gazit
Protein misfolding and aggregation have been associated with several human disorders, including Alzheimer's, Parkinson's and Huntington's diseases, as well as senile systemic amyloidosis and Type II diabetes. However, there is no current disease-modifying therapy available for the treatment of these disorders. In spite of extensive academic, pharmaceutical, medicinal and clinical research, a complete mechanistic model for this family of diseases is still lacking. In this review, we primarily discuss the different types of small molecular entities which have been used for the inhibition of the aggregation process of different amyloidogenic proteins under diseased conditions...
May 9, 2017: Future Medicinal Chemistry
Farzad Mehrabi, Yaghoub Pourshojaei, Alireza Moradi, Mohammad Sharifzadeh, Leila Khosravani, Reyhaneh Sabourian, Samira Rahmani-Nezhad, Maryam Mohammadi-Khanaposhtani, Mohammad Mahdavi, Ali Asadipour, Hamid Reza Rahimi, Setareh Moghimi, Alireza Foroumadi
AIM: A series of 2-benzylidene-benzofuran-3-ones were designed from the structures of Ebselen analogs and aurone derivatives and synthesized in good yields. MATERIALS & METHODS: The target compounds were prepared by the condensation reaction between appropriate benzofuranones with amino alkoxy aldehydes and evaluated as cholinesterase inhibitors by Ellman's method. RESULTS: The in vitro anti-acetylcholinesterase (AChE)/butyrylcholinesterase activities of the synthesized compounds revealed that 7e (IC50 = 0...
May 9, 2017: Future Medicinal Chemistry
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