Current Topics in Medicinal Chemistry - Volume 17, Issue 19, 2017

Background: Despite a reduction in the global burden of malaria, the disease remains responsible for 214 million cases and 438,000 deaths annually with 88% of the mortality occurring in sub-Saharan Africa. Malaria control largely depends on effective chemotherapy. However, the historic and current emergence and spread of multi-drug resistant parasite strains provides significant challenges to malaria control and consequently, reduction of malaria-associated morbidity and mortality. Combating parasite drug resistance requires pharmacological compounds that target both known and novel metabolic pathways that are crucial for parasite survival. In addition, the identification of novel therapeutic agents that target distinct molecular pathways, apart from those of the conventional antimalarials, offers an approach for minimizing drug resistance. Conclusion: This review summarizes current anti-malarial approaches and strategies, therapeutic efficacy for conventional and non-conventional antimalarials, parasitic targets, and the mechanisms responsible for the development of drug resistance.

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

Background: Despite the substantial progress over the time, malaria remains a major public health concern and causing hundreds of thousands of deaths. Resistance to the available antimalarial therapy increases threat to the global public health. Objective: Overview of currently available antimalarials. Method: Literary survey. Results: The summarized data about different types of antimalarial therapies and their efficiency and modes of action. Conclusion: Despite the seemingly large number of the drugs currently available for malaria treatment, this arsenal is limited due to the narrow variation of their mechanism of action.

Background: Phosphoinositides (PIs) and their derivatives are essential cellular components that form the building blocks for cell membranes and regulate numerous cell functions. Specifically, the ability to generate myo-inositol 1,4,5-trisphosphate (InsP3) via phospholipase C (PLC) dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to InsP3 and diacylglycerol (DAG) initiates intracellular calcium signaling events representing a fundamental signaling mechanism dependent on PIs. InsP3 produced by PI turnover as a second messenger causes intracellular calcium release, especially from endoplasmic reticulum, by binding to the InsP3 receptor (InsP3R). Various PIs and the enzymes, such as phosphatidylinositol synthase and phosphatidylinositol 4-kinase, necessary for their turnover have been characterized in Apicomplexa, a large phylum of mostly commensal organisms that also includes several clinically relevant parasites. However, InsP3Rs have not been identified in genomes of apicomplexans, despite evidence that these parasites produce InsP3 that mediates intracellular Ca2+ signaling. Conclusion: Evidence to supporting IP3-dependent signaling cascades in apicomplexans suggests that they may harbor a primitive or non-canonical InsP3R. Understanding these pathways may be informative about early branching eukaryotes, where such signaling pathways also diverge from animal systems, thus identifying potential novel and essential targets for therapeutic intervention.

Introduction: The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models. Conclusion: A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions.

Background: The viruses responsible for mosquito-borne diseases are on an exploring mode, expanding their horizon, adapting to the situation and comfortably making their presence felt globally, from South Africa to Asia, Europe and United States. The current global scenario and recent documentations indicate towards the real monsters, outbreak of Zika, dengue and chikungunya viruses. Zika, dengue and chikungunya viruses are positive sense single-stranded RNA arbovirus and so their initial symptoms are almost 80% similar and all three are spread by mosquitos which bite during the day. Zika virus may damage brain by targeting the neuron cells in babies, and thereby it is very perilous to pregnant women. Dangerous Type: A less common but highly dangerous type of dengue is one which causes haemorrhagic fever and shock syndrome which are lethal. Chikungunya is not as lethal as Zika and dengue are, but it triggers joints pain which could last for months and even for years. Conclusion: The vaccines against Zika, dengue and chikungunya viruses are at different stages of development. The challenges associated with the epidemic wave of Zika, dengue and chikungunya viruses have been explained and the current status of drug/ vaccine development against these viruses has been reviewed.

Introduction: The family of calcium-dependent protein kinases (CDPKs) carries a kinase domain fused to a calmodulin-like domain. The presence of protein kinases devoid of clear mammalian eukaryotic protein kinase orthologues makes them potential targets for therapeutic development. Recent studies on CDPKs have inspired an important primary regulator of calcium (intracellular Ca2+ signaling), which is extensively reported to play a critical role in various stages of the apicomplexan life cycle such as microneme secretion of adhesions, cell invasion, gamete maturation, gliding motility and egress of Plasmodium Spp. Conclusion: Understanding and identifying these essential cytoregulatory components of the parasite is important for drug targets development and therapeutic intervention.

Introduction: Mosquito borne diseases continue to propagate and cause millions of deaths annually. They are caused either by protozoan parasites such as Plasmodium, Toxoplasma or by flaviviruses including Dengue and Zika. Among the proteome of such parasitic organisms, proteases play essential roles in events such as host invasion, hemoglobin hydrolysis, replication and immune evasion. Plasmepsin V (PMV), an endoplasmic reticulum resident aspartic protease of Plasmodium spp., is involved in the export of ~400 proteins containing the conserved Plasmodium Export Element motif (PEXEL). Interactions and cleavage of PEXEL proteins by PM V is necessary for export to and across the parasitophorous vacuole membrane. Protease System: Similarly in flaviviruses, a two-component protease system consisting of nonstructural proteins, NS2B and NS3, interacts with other non-structural proteins and plays a major role in viral replication, polyprotein cleavage and virion particle assembly. Thus, proteases involved in indispensable roles in pathogen machinery can be considered as attractive drug targets. Inhibitors against proteases are being used in clinical trials for other communicable and non-communicable diseases. Currently, hydroxyethylamine based inhibitors targeting the catalytic site of PM V with picomolar inhibitory concentrations have been tested in vitro. Conclusion: For recently characterized disease such as Zika, no known treatments exist while compound such as Policresulen has high affinity for Dengue NS2B/NS3 complex. Understanding proteases structure-function relationship and protease-inhibitor interactions can provide new insights for novel chemotherapeutic strategies.