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Current Topics in Medicinal Chemistry

Ping Wang, Jing Cheng, Cong-Cong Liu, Kai Tang, Feng Xu, Zhiqiang Yu, Bin Yu, Junbiao Chang
Metallo-β-lactamases (MBLs) are a family of Zn(II)-dependent enzymes that can hydrolyze almost allβ-lactam antibiotics. Horizontal transferofthe genes encodingMBLsamong Gram-negative bacteria pathogens has led to the emergence of extensively drug-resistantpathogens, which now represent a major threat to human health.As there is not to date yet a clinicallyavailable MBL inhibitor, the discovery of new MBL inhibitors has great urgency. This review highlights the recent developments in the discovery of small-molecule MBL inhibitors...
May 17, 2018: Current Topics in Medicinal Chemistry
Chiara Testa, Anna Maria Papini, Michael Chorev, Paolo Rovero
The long lasting impetus to design novel modes of macrocyclization, and their implementation into a wide range of bioactive peptides, originates from their contributions to the restriction of conformational space and the stabilization of preferential bioactive conformations that support higher efficacy and binding affinity to cognate macromolecular targets, improved specificity and lowering susceptibility to enzymatic degradation processes. Introducing CuI-catalyzed azide-alkyne cycloadditon (CuAAC), a prototypical click reaction, to the field of peptide sciences as a bio-orthogonal reaction that generates a disubstituted-[1,2,3]triazol-1-yl moiety as a pseudopeptidic bond that is peptidomimetic in nature, paved the way to its wide spread application as a new and promising mode of macrocyclization...
May 17, 2018: Current Topics in Medicinal Chemistry
Robert A Hillman, Jonathan W Nadraws, Michael A Bertucci
Anomalous protein-protein interactions (PPIs) have been correlated to a variety of disease states, such as cancer, infectious disease, neurological disorders, diabetes, endocrine disorders and cardiovascular disease. Stapled peptides are an emerging intervention for these PPIs due to their improved structural rigidity and pharmacokinetic properties relative to unstapled peptides. This review details the most recent advances in the field of stapled peptide therapeutics, including the increasing variety of PPIs being targeted and types of peptide staples being employed...
May 17, 2018: Current Topics in Medicinal 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
Samuel J S Rubin, Nir Qvit
Backbone-cyclized peptides and peptidomimetics integrate the biological activity and pharmacological features necessary for successful research tools and therapeutics. In general, these structures demonstrate improved maintenance of bioactive conformation, stability and cell permeability compared to their linear counterparts, while maintaining support for a variety of side chain chemistries. We explain how backbone cyclization and cycloscan techniques allow scientists to cyclize linear peptides with retained or enhanced biological activity and improved drug-like features...
May 17, 2018: Current Topics in Medicinal Chemistry
Horrick Sharma
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH 1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumor types, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyze αKG conversion to (R)-2-hydroxyglutarate ((R)-2HG)...
May 17, 2018: Current Topics in Medicinal Chemistry
Ryan W Mull, Anthony Harrington, Lucia A Sanchez, Yftah Tal-Gan
Cyclic peptide scaffolds are key components of signal transduction pathways in both prokaryotic and eukaryotic organisms since they act as chemical messengers that activate or inhibit specific cognate receptors. In prokaryotic organisms these peptides are utilized in non-essential pathways, such as quorum sensing, that are responsible for virulence and pathogenicity. In the more evolved eukaryotic systems, cyclic peptide hormones play a key role in the regulation of the overall function of multicellular organisms, mainly through the endocrine system...
May 17, 2018: Current Topics in Medicinal Chemistry
Preet Amol Singh, Sapna D Desai, Jasbir Singh
As per WHO reports, about three-quarters (65-80%) of the world's population seeks plants or plant-derived natural products for various diseases. The slow discovery of new synthetic molecules and rising resistance in microbes against existing ones has triggered an alarm for speeding up the development process for new molecules. Traditional system(s) of medicine and plant resources has been foresighted again by researchers to circumvent the situation. This review represents various plant genera which, either as a whole plant or their parts, have been reported possessing antimicrobial properties during the last decade...
May 16, 2018: Current Topics in Medicinal Chemistry
Nestor M Carballeira, Christian Morales-Guzman, Ester Alvarez-Benedicto, Zally Torres-Martinez, Yamixa Delgado-Reyes, Kai H Griebenow, Arthur D Tinoco, Rosa M Reguera, Yolanda Perez-Pertejo, Ruben Carbajo-Andres, Rafael Balana-Fouce
The first total synthesis of -phenyl 6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16-phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6-decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6-decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields...
May 16, 2018: Current Topics in Medicinal Chemistry
Ozkan Varan, Hakan Babaoglu, Berna Goker
Depressive disorders, are not only common but also among the leading causes of disability worldwide. They are associated with increased incidences of various other diseases. It has been shown that in patients with autoimmune diseases, when depression coexists, the quality of life is worse and medical treatment and management is compromised. Depression-like symptoms, such as fatigue and disinterest are also common in inflammatory rheumatic diseases and often associated with poor quality of life. Medical therapy targeting inflammation results in alleviation of these symptoms in many patients...
May 15, 2018: Current Topics in Medicinal Chemistry
Carolina L Bellera, Maria L Sbaraglini, Alan Talevi
Neglected diseases comprise a number of infectious diseases historically endemic to low- and middle-income countries, though recently they have spread to high-income countries due to human migrations. In the past, pharmaceutical companies have shown hesitant to invest in these health conditions, due to the limited return on investment. As a result, the role of the academic sector and non-for-profit organizations in the discovery of new drugs for neglected diseases has been particularly relevant. <p> Here, we review recent applications of modern drug discovery technologies in the field of neglected diseases, including high-throughput screening, in silico screening and computer-aided drug design...
May 9, 2018: Current Topics in Medicinal Chemistry
Andre Lacerda Braga Teles, Roseane R Silva, Michelle Ko, Glaucio Monteiro Ferreira, Samuel da Rocha Pita, Gustavo Henrique Goulart Trossini, Paulo Carvalho, Marcelo Santos Castilho
Schistosoma mansoni is responsible for virtually all reported cases of schistosomiasis in Latin America and the emergence of praziquantel- and oxaminiquine-resistant strains makes it urgent to develop new schistosomicide agents. Dihydrofolate reductases (DHFR) from bacteria and protozoan parasites are considered validated macromolecular targets for this goal, but S. mansoni DHFR (SmDHFR) has been largely overlooked. To fill this gap in knowledge, the present work describes optimized conditions to carry out thermal shift assays with SmDHFR, as well as a balanced kinetic assay that supports 2,4-diaminopyrimidine derivatives as SmDHFR inhibitors...
May 9, 2018: Current Topics in Medicinal Chemistry
Vanessa Leiria Campo, Marcelo Fiori Marchiori, Ivone Carvalho
Chagas disease is still a worldwide threat, with estimated 6 to 7 million infected people, mainly in Latin America. Current treatments still rely only on benznidazol and nifurtimox, drugs with poor efficacy in chronic infection phase and recognized toxicity. Thus, there is an urgent need for new therapeutic agents against this disease. In this review we present an updated selection over the last decade of synthetic glycoconjugates as anti-trypanosomal agents, properly addressed as monosaccharide- and disaccharide-based agents, and multivalent-based derivatives, disclosing relevant methods for their synthesis, along with their activities on T...
May 9, 2018: Current Topics in Medicinal Chemistry
Pedro H Scarpelli Pereira, Chiara Curra, Celia R S Garcia
Parasites of Plasmodium genus are responsible for causing malaria in humans. Resistant strains to all available antimalarials can be found in several locations around the globe, including parasites resistant to the latest generation of combination drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts such as a vertebrate one and the mosquito vector, thus it has the ability to adapt to very extreme and different environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells thus making very difficult the study of the biology of the parasite and the identification of targets for drug development affecting all stages...
April 27, 2018: Current Topics in Medicinal Chemistry
Juan A Bisceglia, Maria C Mollo, Nadia Gruber, Liliana R Orelli
Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development...
April 27, 2018: Current Topics in Medicinal Chemistry
Leonardo L G Ferreira, Rafaela S Ferreira, David L Palomino, Adriano D Andricopulo
The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T...
April 27, 2018: Current Topics in Medicinal Chemistry
Lorenzo Lo Muzio, Fatima Ardito
BACKGROUND: The squamous cell carcinoma of the tongue (TSCC) is the most frequent cancer of oral cavity often characterized by poor prognosis. Conventional therapies are not very efficient and often may cause serious side effects. In this contest, introduction of natural substances as possible adjuvant in the treatment and prevention of cancer is becoming a relevant topic. In fact, curcumin has been used for decades in Chinese traditional medicine for its beneficial effects. Curcumin has anti-cancer properties in many tumors however, its action on the tongue carcinoma is not entirely clear and many other investigations are necessary...
April 12, 2018: Current Topics in Medicinal Chemistry
Maria Teresa Junqueira Garcia, Fabia Leal Lopes Vasconcelos, Chloe Patricia Raffier, Michael Stephen Roberts, Jeffrey Ernest Grice, Heather Ann Elizabeth Benson, Vania Rodrigues Leite-Silva
It is critical to develop an effective understanding of the interaction between the drug, delivery system and skin in order to predict and assess skin penetration and permeation. Experimental models for the assessment of topical and transdermal delivery systems must permit evaluation of these complex interactions. Whilst in the past animal models were commonly used, recent regulatory guidelines, based on 3R principles (refinement, reduction, replacement), encourage the rational use of animals. Alternative methods have been proposed for use in the development of topical and transdermal delivery systems which are often used in combination...
April 12, 2018: Current Topics in Medicinal Chemistry
Ana Claudia Torrecilhas, Patricia Xander, Karen Spadari Ferreira, Wagner Luiz Batista
The neglected tropical diseases (NTDs) are caused by several parasites, fungi, bacteria and viruses and affect more than one billion people in the world. The control and prevention against NTDs need implementation of alternative methods for testing new compounds against these diseases. For the implementation of alternative methods, it is necessary to apply the principles of replacement, reduction and refinement (the 3Rs) for the use of laboratory animals. Accordingly, the present review addressed a variety of alternative models to study the infections caused by protozoa and fungi...
April 12, 2018: Current Topics in Medicinal Chemistry
Telma Mary Kaneko, Natalia Mencacci Esteves-Pedro, Kenji Sugibayashi, Marcio Ferrari, Elissa A Ostrosky, Bianca da Silva Sufi, Monica Beatriz Mathor, Felipe R Lourenco, Andre R Baby, Vladi Olga Consiglieri
It is challenging to disperse lipophilic substances in a validated cytotoxicity assay, especially for compounds with log Kow greater than or equal to 5 that may show false negative results. The purpose of this study was to explain the challenges in conducting a cytotoxicity validated test of lipophilic substances: Minthostachys setosa, Pimenta pseudocaryophyllus, and Drimysbrasiliensis essential oils. Additionally, we compared the equivalence of Neutral Red (NR) and 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H -tetrazolium, inner salt (MTS) in detecting cell viability...
April 10, 2018: Current Topics in Medicinal Chemistry
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