Current Topics in Medicinal Chemistry - Volume 18, Issue 5, 2018

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 the study of the biology of the parasite and the identification of targets for drug development affecting all stages very difficult. It was shown that host molecules, such as melatonin and derivatives, have a role in the progression and regulation of the parasite cell cycle; In fact, when the parasite is exposed to melatonin there is an increase in transcription levels of genes encoding for proteins related to the Ubiquitin Proteasome (UPS) System. This system is essential for the survival of the parasite, and drugs such as bortezomib, MLN-273, ZL3B, epoxomicins and salinosporamides are capable of eliminating the parasite by inhibiting the degradation of proteins via the proteasome system. In addition, the Plasmodium UPS shows low similarity to the ubiquitin proteasome system in Humans; the identification of unique targets to be used for therapeutic molecules development increases the importance of UPS studies in malaria challenging. Drugs that cause oxidative stress, such as artemisinin, show a strong synergistic effect with proteasome inhibitors, increasing the possibilities of combined therapies, which are more effective with lower concentration of drugs. Thus, the study of the mechanism of action of the UPS and the identification of potential targets for new drugs development are promising alternative strategies to fight the drug-resistance problem in malaria parasites.

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. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

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 not-for-profit organizations in the discovery of new drugs for neglected diseases has been particularly relevant. 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. The suitability and perspectives of each approach are discussed depending on the context, along with the technology and translational gaps influencing them.

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 monosaccharideand disaccharide-based agents, and multivalent-based derivatives, disclosing relevant methods for their synthesis, along with their activities on T. cruzi and its trans-sialidase (TcTS). In addition, synthetic glycoconjugates as potential vaccines and diagnostic antigens against T. cruzi are also reported.

Introduction: 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. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme. Results: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions. Conclusion: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure-based drug design efforts in HAT drug discovery.

Introduction: 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. The most potent inhibitor (2a) shows a large shift of the melting temperature (ΔTm = + 8 ± 0,21 ºC) and a low micromolar IC50 value (12 ± 2,3 μM). Both thermal shift and classical kinectic assay suggest that 2a binds to the substrate binding site (competitive inhibition mechanism). This information guided docking and molecular dynamics studies that probed 2a interaction profile towards SmDHFR. Conclusion: In conclusion, this work not only provides standardized assay conditions to identify SmDHFR inhibitors, but also describes the binding profile of the first low micromolar inhibitor of this macromolecular target.

Introduction: The first total synthesis of ω-phenyl Δ6 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. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z-decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the ω-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 ± 1 μM. On the other hand, among the C10 acids, the ω-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 ± 2 μM) towards A549. Results: Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death. Conclusion: The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 μM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 μM) and L. infantum promastigotes (IC50 = 60- 70 μM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum ω- phenylated acid of the series.