Current Topics in Medicinal Chemistry - Volume 18, Issue 18, 2018

Dengue like any neglected tropical disease affects a large part of the world population. In this disease, the infection is caused by arboviruses transmitted by the A. aegypti and A. albopictus mosquito, in which its most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic of such as fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In the studies shown, in silico tests were performed as molecular docking, functional density analysis, molecular orbitals energies with the analyses of the interactions between bioactives and the targets studied. However, in addition to discussing the fight against dengue virus infection through different routes, in this paper, some in silico results of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism.

Current review article focuses on dengue, which is one of the most fatal infectious illnesses and is considered to be a worldwide threat. The paper covers essential topics including an overview on neglected tropical diseases with specific emphasis on Dengue fever, mosquito's cycle of life and mechanism of infection, adaptive response, and different stages in dengue immunopathogenesis. The current work is also dedicated to the thorough study of dengue outbreak across the globe with a narrowed study to tropical and subtropical regions. Moreover, this review article demonstrates the correlation between climate factors and dengue incidence. Furthermore, we present an overview of the detection strategies of dengue including the latest developments in commercial and non-commercial platforms. Several attempts in developing an effective vaccine to protect individuals from dengue infection and the stage of clinical trials are gathered in the present work as well. Future directions including bio-control are also discussed in this review article. In an overall view, effective management of Dengue is a multidisciplinary task that requires international involvement from different backgrounds and expertise to address this global concern. This review article briefly portrays some of these connecting areas across the disciplines while many other perspectives remain uncovered.

Background: Many of the tropical diseases are neglected by the researchers and medicinal companies due to lack of profit and other interests. The Drugs for Neglected Diseases initiative (DNDi) is established to overcome the problems associated with these neglected diseases. According to a report published by the WHO, leprosy (Hansen's disease) is also a neglected infectious disease. Methods: A negligible amount of advancements has been made in last few decades which includes the tools of diagnosis, causes, treatment, and genetic studies of the bacterium (Mycobacterium leprae) that causes leprosy. The diagnosis of leprosy at earlier stages is important for its effective treatment. Recent studies on vitamin D and its receptors make leprosy diagnosis easier at earlier stages. Skin biopsies and qPCR are the other tools to identify the disease at its initial stages. Results: Until now a specific drug for the treatment of leprosy is not available, therefore, Multi-Drug Therapy (MDT) is used, which is hazardous to health. Besides Mycobacterium leprae, recently a new bacterium Mycobacterium lepromatosis was also identified as a cause of leprosy. During the last few years the genetic studies of Mycobacterium leprae, the role of vitamin D and vitamin D receptors (VDR), and the skin biopsies made the treatment and diagnosis of leprosy easier at early stages. The studies of micro RNAs (miRNAs) made it easy to differentiate leprosy from other diseases especially from tuberculosis. Conclusion: Leprosy can be distinguished from sarcoidosis by quantitative study of reticulin fibers present in skin. The treatment used until now for leprosy is multi-drug treatment. The complete genome identification of Mycobacterium leprae makes the research easy to develop target specified drugs for leprosy. Rifampicin, identified as a potent drug, along with other drugs in uniform multi-drug treatment, has a significant effect when given to leprosy patients at initial stages. These are effective treatments but a specific drug for leprosy is still needed to be identified. The current review highlights the use of modern methods for the identification of leprosy at its earlier stages and the effective use of drugs alone as well as in combination.

Background: Neglected tropical diseases (NTDs) are communicable diseases caused by a group of bacteria, viruses, protozoa and helminths prevalent in more than 145 countries that affect the world's poverty stricken populations. WHO enlists 18 NTDs amongst people living in endemic areas having inaccessibility to preventive measures. Steps to reduce the global disease burden of the NTDs need attention at multi-factorial levels. Control programmes, mass drug administrations, transmission checks, eradication surveillances and diagnoses are some of them. The foremost in this list is confirmatory diagnosis. A comprehensive summary of the innovative, high-impact, multiplexed, low-cost diagnostic tools developed in the last decade that helped to meet the needs of users can depict a holistic approach to further evaluate potential technologies and reagents currently in research. Major Advancements: A literature survey based on developing nano-biotechnological platforms to meet the diagnostic challenges in NTDs towards development of a useful point-of-care (POC) unit is reported. However, in order to pave the way for complete eradication more sensitive tools are required that are user-friendly and applicable for use in endemic and low-resource settings. There are various novel research progresses/advancements made for qualitative and quantitative measurement of infectious load in some diseases like dengue, Chagas disease and leishmaniasis; though further improvements on the specificity and sensitivity front are still awaited. Strategies to combat the problem of antimicrobial drug resistance in diagnosis of NTDs have also been put forward by various research groups and organizations. Moreover, the state-of-the-art “omics” approaches like metabolomics and metagenomics have also started to contribute constructively towards diagnosis and prevention of the NTDs. Conclusion: A concrete solution towards a single specimen based common biomarker detection platform for NTDs is lacking. Identifying robust biomarkers and implementing them on simple diagnostic tools to ease the process of pathogen detection can help us understand the obstacles in current diagnostic measures of the NTDs.

Despite being one of the most commonly used drugs, the molecular mechanism of action of the anthelmintic praziquantel remains unknown. There are some unusual features of this drug. Critically, widespread resistance to praziquantel has not developed despite decades of use. Here, we set out some challenges in praziquantel research and propose some provocative hypotheses to address these. We suggest that praziquantel may have multiple pharmacologically relevant targets and the effects on these may synergise to produce an overall, detrimental effect on the parasite. Praziquantel also acts on a number of host proteins and we propose that these actions are important in the drug's overall mechanism. Although the drug is largely used in the treatment of human and domestic animal worm infections, there is a considerable “grey literature” along with some academic studies which may have been overlooked. It appears that praziquantel may be effective against hydra. It may also be effective against some unicellular parasites such as Giardia spp. Further, scientific work on these understudied areas may be useful in understanding the molecular mechanism in Trematoda. The lack of widespread resistance suggests that praziquantel may act, at least in part, on a protein-protein interaction. Altered drug metabolism or enhanced drug efflux are the most likely ways resistance may arise. There is a critical need to understand the biochemical pharmacology of this drug in order to inform the discovery of the next generation of anthelmintic drugs.

Background: Dengue fever, a major public health problem in the tropical and sub-tropical countries caused by the infection of Dengue virus transmitted by the anthropod vectors. The dengue virus infection is represented as the “Neglected Tropical Diseases” by the world health organization. The structural protein E binds to the receptor on the host cell surface during infection and the binding directs to the endocytic pathway. The conformational change of the envelope protein helps to infuse the viral lipid membrane and delivers the viral genome into the cytosol. No specific treatments are available till date and development of the vaccine for the DENV is challenging due to the immunization and longlasting protection against all four serotypes. Hence, identification of potent inhibitors would overlay the therapeutics against the mediated diseases. Objective: Our study focuses on developing the novel potent inhibitors to inhibit the viral attachment and membrane fusion of the Dengue virus Envelope protein. Methods: The crystal structure of Dengue Envelope protein has been retrieved from the protein data bank and optimized through Schrödinger. The structure-based virtual screening based on the cocrystallised ligand has been carried out with the small molecule libraries, and based on the docking score, interaction and energy value best complexes were selected. The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation. Results: Around 55 molecules from the three databases were identified as potential binders to the envelope protein and the docking studies revealed that the top compounds possess strong interaction with the good energies. The Molecular electrostatic surface potential of the top five compounds states that the interactions were observed mostly in the electropositive region. Finally, the best 5 compounds carried further for molecular dynamics simulations exposed that they were highly stable and no loss of interactions was observed between those complexes. Conclusion: Hence, from the results, it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be novel and potent candidates to inhibit the DENV envelope protein.

Background: Leishmaniasis, which is classified by the World Health Organization (WHO) as one of the Neglected Tropical Diseases (NTDs) faces several challenges in terms of successful chemotherapy and novel drug developments. Objective: The aim of the present study was to develop a Self-Emulsifying Drug Delivery System (SEDDS) for the hydrophobic polyphenol pigment curcumin to enable it for its potential use in cutaneous and mucocutaneous leishmaniasis. Methods: Two Curcumin-loaded formulations SNEDD-A and B, were developed. Both were characterized by the droplet size, PDI and zeta potential and evaluated for the cytotoxicity on Caco-2 cell lines and through hemolysis test on red blood cells. The spreading potential of the formulations was checked over buccal mucosa and damaged skin model. Antileishmanial activities were performed against promastigote, axenic amastigote and macrophage harbored amastigotes of Leishmania tropica parasite. Results: SNEDDS-A and B had minor differences in physical characteristics. In the toxicological assay, the viability of the Caco-2 cells was 87.5 % for SNEDDS-A and 88.9% for SNEDDS-B while both caused 1-2% hemolysis. Both had remarkable spreading potential, covering 8cm2 of buccal mucosa and damaged the skin for less than 45 minutes. The Antileishmanial activities of the SNEDDS-A in terms of IC50 were 0.13 μg/ml and 0.25 μg/ml against promastigote and amastigote, respectively while IC50 values of SNEDDS-B were 0.18 μg/ml and 0.27 μg/ml against promastigote and amastigote, respectively. Both the formulations killed 100% of the macrophage harbored Leishmania tropica parasites at a concentration of 4.4 μg/ml. Conclusion: Our results demonstrate that both the SEDDS formulations of curcumin have the potential to provide a promising tool for curcumin for its use through topical routes in the treatment of cutaneous and mucocutaneous leishmaniasis.

Background: Nowadays, malaria is still one of the most important and lethal diseases worldwide, causing 445,000 deaths in a year. Due to the actual treatment resistance, there is an emergency to find new drugs. Objective: The aim of this work was to find potential inhibitors of phosphoglycerate mutase 1 from P. falciparum. Results: Through virtual screening of a chemical library of 15,123 small molecules, analyzed by two programs, four potential inhibitors of phosphoglycerate mutase 1 from P. falciparum were found: ZINC64219552, ZINC39095354, ZINC04593310, and ZINC04343691; their binding energies in SP mode were -7.3, -7.41, -7.4, and -7.18 kcal/mol respectively. Molecular dynamic analysis revealed that these molecules interact with residues important for enzyme catalysis and molecule ZINC04343691 provoked the highest structural changes. Physiochemical and toxicological profiles evaluation of these inhibitors with ADME-Tox method suggested that they can be considered as potential drugs. Furthermore, analysis of human PGAM-B suggested that these molecules could be selective for the parasitic enzyme. Conclusion: The compounds reported here are the first selective potential inhibitors of phosphoglycerate mutase 1 from P. falciparum, and can serve as a starting point in the search of a new chemotherapy against malaria.