Current Medicinal Chemistry - Volume 25, Issue 39, 2018

The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such as African sleeping sickness, Chagas’ disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets.

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

Background: Parasite diseases are a huge burden on human health causing significant morbidity and mortality. However, parasite structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasite derived proteins and have often relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. Results: In this review, we discuss the challenges associated with the structural determination of parasite proteins including the difficulties in obtaining sufficient quantities of protein. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasite protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in anti-parasite drug discovery. Conclusions: This review reports the progress that has been made in obtaining sufficient quantities of proteins for structural studies and the role EM may play in future structure based drug design programs. The outlook for future structure based drug design programs against some of the most devastating parasite diseases looks promising.

The discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to the discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bioinformatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of the development of multitarget approaches in quantitative structure-activity relationships (mt-QSAR) for CNS drug discovery; and describes applications of multi-target approaches in molecular modelling (which can be called mt-MM), as well as perspectives for multi-target approaches in bioinformatics in relation to Alzheimer's disease.

Dimebon (or Latrepirdine) was initially used as an anti-histamergic drug but later new therapeutic properties were rediscovered, adding to a growing body of “old” agents with prominent neuroprotective effects. In the present manuscript, we are focusing on our latest study on Dimebon with regard to brain's pathological processes using in vivo proteinopathy models. In the study, neurodegenerative pathology has been attributed to a group of aggregate-prone proteins: hyperphosphorylated tau, fused in sarcoma and γ-synuclein , which are involved in a number of neurological disorders. We have also presented our in vitro model based on overexpression of an aberrant mutant form of transactive response DNA binding 43 kDa protein in cultured SH-SY5Y neuroblastoma cells. Dimebon treatment followed by the activation of autophagy markers resulted in reduced number of inclusion containing cells. The most significant effects of Dimebon appeared to be on the improving cellular energy balance, mitochondria stability by increasing the threshold for nonselective mitochondrial pore opening as well as on increased calcium retention capacity while reducing lipid peroxidation. The therapeutic potential of Dimebon and newly designed analogs show disease modifying properties and could be used to treat neurodegenerative disorders. In addition, new data hint on a possible anti-aging effect and potential application of Dimebon for treatment of anxiety, ischemia and depression. Overall, our findings suggest that the most pronounced effect of Dimebon was observed when treatment was started at the early stages of disease onset and this factor needs to be taken into account while planning future clinical trials.

Neurodegenerative disorders (NDDs) like Alzheimer's disease, Parkinson’s disease and Huntington’s disease are a heterogeneous group of disorders with the progressive and severe loss of neurons. There are no full proof cures for these diseases, and only medicines are available that can alleviate some of the symptoms. Developing effective treatments for the NDDs is a difficult but necessary task. Hence, the investigation of monoterpenoids which modulate targets applicable to many NDDs is highly relevant. Many monoterpenoids have demonstrated promising neuroprotective activity mediated by various systems. It can form the basis for elaboration of agents which will be useful both for the alleviation of symptoms of NDDs and for the treatment of diseases progression and also for prevention of neurodegeneration. The further developments including detections of monoterpenoids and their derivatives with high neuroprotective or neurotrophic activity as well as the results of qualified clinical trials are needed to draw solid conclusions regarding the efficacy of these agents.

Diet is an essential factor affecting the development of and risk for diabetes mellitus. In search of preventative and therapeutic strategies, the potential role of certain foods and their bioactive compounds to prevent the pathogenesis associated with metabolic diseases is to be considered. Human consumption of anthocyanins is among the highest of all flavonoids. Epidemiological studies have suggested that the consumption of anthocyanins lowers the risk of diabetes and diabetic complications. Anthocyanins are important natural bioactive pigments responsible for red to blue colour of fruits, leaves, seeds, stems and flowers, which are present in a variety of plant species particularly in berries and cherries. A large number of bioactive anthocyanins, such as cyanidin, malvidin, delphinidin, pelargonidin, peonidin, petunidin and their metabolites have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion and sensitivity, on the enzymes involved in glucose metabolism, gene expressions, inflammatory mediators, glucose transporters in progression of diabetes and associated complications, such as diabetic retinopathy, nephropathy, neuropathy and diabetic vascular diseases. The versatility of the anthocyanins provides a promising approach for diabetes management than synthetic drugs. Here we summarize the effect of several anthocyanins on many in vitro, in vivo and clinical studies and also reveal the mechanisms which could prevent or reverse the underlying mechanisms of diabetic pathologies including promotion of antioxidant, antihyperlipidemic, anti-inflammatory and anti-apoptotic activities.

Patients with Parkinson’s disease (PD) are looking forward to new therapeutic strategies that may gradually decelerate the rate of neurodegenerative decline, associated with mobility restrictions and related morbidity. Its continuous neurodegenerative process, exacerbated by genetic mutations or environmental toxins, involves a progressive reduction in the dopamine neurotransmission levels, synaptic uptake density, oxidative glucose intake, deficient striatal lactate accumulation and chronic inflammation. Over the last decade, novel bioproducts have received considerable interest due to their unique potential of unifying nutritional, safety and therapeutic natural effects. Some nutraceuticals play a crucial role in the control of the signaling transduction pathways in neurotransmission and inflammation affected in PD, and some natural compounds can beneficially interact with each one of these biological mechanisms to slow down disease progression. Atremorine, a novel plant-derived nutraceutical, probably with a neuroprotective effect in the dopaminergic neurons of the substantia nigra (pars compacta), is a prototype of this new category of bioproducts with potential effects in PD. The major focus of this review will be on the current knowledge and biomedical investigation strategies through a plant-derived neuroprotective approach to improve life quality in PD patients, being of paramount importance for health providers, caregivers and the patients themselves.

A number of biological and clinical characteristics typical of late life depression (LLD) have been suggested by recent research findings. The close association of LLD with cognitive impairment is now well documented and evidenced. However, it is still not clear whether it is depression that leads to cognitive decline, and in more severe cases, to dementia. The work presented in this review article suggests that depression and dementia frequently and strongly copresent, even if the causality remains largely opaque.

Over the years, natural products have shown success as antidiabetics in in vitro, in vivo studies and clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs, and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Background: Metabolic disorders comprise a set of different disorders varying from epidemic diseases such as diabetes mellitus to inborn metabolic orphan diseases such as phenylketonuria. Despite considerable evidence showing the importance of the computational methods in discovery and development of new pharmaceuticals, there are no systematic reviews outlining how they are utilized in the field of metabolic disorders. This review aims to discuss the necessity of the development of web-based tools and databases by integration of available information for solving Big Data problems in network pharmacology of metabolic disorders. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. Results: The alterations in metabolic pathways cause various cardiovascular, hematological, neurological, gastrointestinal, immune disorders and cancer. In this regard, informatics, Big Data and modeling techniques aid in the design of novel therapeutic agents for metabolic diseases by addressing various Big Data problems in the network polypharmacology (drugs/pharmaceutical agents, proteins, genes, diseases, bioassays, ADMET and metabolic pathways), identification of privileged scaffolds, developing new diagnostic biomarkers, understanding the pathophysiology of disease and progress in personalized medicine. Conclusion: The recent advances of developing pharmaceutical agents for various metabolic disorders by considering their pathogenesis, mechanisms of action, therapeutic and adverse effects have been summarized. We have highlighted the role of computational techniques, drug repurposing, and network-based polypharmacological approaches in the identification of new/existing medicines with improved drug-likeness properties for the rare metabolic disorders.