The termneglected diseasesrefers to a group of infections caused by various classes of pathogens, including protozoa, viruses, bacteria, and helminths, most often affecting impoverished populations without adequate sanitation living in close contact with infectious vectors and domestic animals. The fact that these diseases were historically not considered priorities for pharmaceutical companies made the available treatments options obsolete, precarious, outdated, and in some cases nonexistent. The use of plants for medicinal, religious, and cosmetic purposes has a history dating back to the emergence of humanity. One of the principal fractions of chemical substances found in plants are essential oils (EOs). EOs consist of a mixture of volatile and hydrophobic secondary metabolites with marked odors, composed primarily of terpenes and phenylpropanoids. They have great commercial value and were widely used in traditional medicine, by phytotherapy practitioners, and in public health services for the treatment of several conditions, including neglected diseases. In addition to the recognized cytoprotective and antioxidative activities of many of these compounds, larvicidal, insecticidal, and antiparasitic activities have been associated with the induction of oxidative stress in parasites, increasing levels of nitric oxide in the infected host, reducing parasite resistance to reactive oxygen species, and increasing lipid peroxidation, ultimately leading to serious damage to cell membranes. The hydrophobicity of these compounds also allows them to cross the membranes of parasites as well as the blood-brain barrier, collaborating in combat at the second stage of several of these infections. Based on these considerations, the aim of this review was to present an update of the potential of EOs, their fractions, and their chemical constituents, against some neglected diseases, including American and African trypanosomiasis, leishmaniasis, and arboviruses, specially dengue.

Chikungunya virus (CHIKV) causes an infectious disease characterized by inflammation and pain of the musculoskeletal tissues accompanied by swelling in the joints and cartilage damage. Currently, there are no licensed vaccines or chemotherapeutic agents to prevent or treat CHIKV infections. In this context, our research aimed to explore the potential in vitro anti-CHIKV activity of acrylamide derivatives. In silico methods were applied to 132 Michael’s acceptors toward the six most important biological targets from CHIKV. Subsequently, the ten most promising acrylamides were selected and synthesized. From the cytotoxicity MTT assay, we verified that LQM330, 334, and 336 demonstrate high cell viability at 40 µM. Moreover, these derivatives exhibited anti-CHIKV activities, highlighting the compound LQM334 which exhibited an inhibition value of 81%. Thus, docking simulations were performed to suggest a potential CHIKV-target for LQM334. It was observed that the LQM334 has a high affinity towards the E3-E2-E1 glycoproteins complex. Moreover, LQM334 reduced the percentage of CHIKV-positive cells from 74.07 to 0.88%, 48h post-treatment on intracellular flow cytometry staining. In conclusion, all virtual simulations corroborated with experimental results, and LQM334 could be used as a promising anti-CHIKV scaffold for designing new drugs in the future.

Background: Methicillin-resistant and vancomycin-resistant Staphylococcus aureus are pathogens causing severe infectious diseases that pose real public health threats problems worldwide. In S. aureus, the most efficient multidrugresistant system is the NorA efflux pump. For this reason, it is critical to identify efflux pump inhibitors. Objective: In this paper we present an update of the new natural and synthetic compounds that act as modulators of antibiotic resistance through the inhibition of the S. aureus NorA efflux pump. Results: Several classes of compounds capable to restoring the antibiotic activity have been identified against resistant-S. aureus strains, acting as NorA efflux pump inhibitors. The most promising classes of compounds were quinolines, indoles, pyridines, phenols, and sulfur-containing heterocycles. However, the substantial degree structural diversity of these compounds makes it difficult to establish good structure-activity correlations that allow design of compounds with more promising activities and properties. Conclusion: Despite substantial efforts put forth in the search for new antibiotic adjuvants that act as efflux pump inhibitors, and despite several promising results, there are currently no efflux pump inhibitors authorized for human or veterinary use, or in clinical trials. Unfortunately, it appears that infection control strategies have remained the same since the discovery of penicillin, and that most efforts remain focused on discovering new classes of antibiotics, rather than trying to prolong the life of available antibiotics, and simultaneously fighting mechanisms of bacterial resistance.

Drug design and discovery is a process that requires high financial cost, as time-consuming. For many years, this process was focused on empirical pharmacology. However, over the years, the approach target-based allowed a significant discovery in this field, initiating the rational design era. In view, to decrease the time and financial cost, the rational drug design benefited by increasing computer engineering and software development, computer-aided drug design (CADD) emerges as a promising alternative. Since the 1970s, this approach was able to identify many important and revolutionary compounds, like protease inhibitors, antibiotics, and others. Many anticancer compounds identified through this approach showed their importance, being CADD essential in any drug discovery campaign. Thus, this perspective paper will show the prominent success cases in this approach and the next stage of drug design. We believe that drug discovery will follow the progress in bioinformatics, using high-performance computing with molecular dynamics protocols faster and effectively. In addition, artificial intelligence and machine learning will be the next process in the rational design of new drugs. Here, we hope that this paper generates new ideas and instigates research groups worldwide to use these methods and stimulate progress in drug design.

: Neglected tropical diseases (NTDs) are a group of approximately 20 diseases that affect part of the population in Sub- and Tropical countries. In the past, pharmaceutical industries and governmental agencies have invested in the control, elimination and eradication of such diseases. Among these diseases, Chagas disease (CD) and Human African trypanosomiasis (HAT) are a public health problem, mainly in the countries from the American continent and sub-Saharan African. In this context, the search for new therapeutic alternatives against such diseases has been growing in recent years, presenting cysteine proteases as the main strategy to discover new anti-trypanosomal drugs. Thus, cruzain and rhodesain enzymes are targets widely studied, since the cruzain is present in all stages of the parasite's life, related to the stages of proliferation and differentiation and infection of macrophages; while the rhodesain is related to the immune defense process. In addition, knowledge about the amino acid sequences and availability of X-ray complexes have stimulated the drug searching against these targets, mainly through molecular modeling studies. Thus, this review manuscript will be addressed to cruzain and rhodesain inhibitors developed in the last 10 years, and which could provide basis for new lead compounds in the discovery of new trypanocidal drugs. We found 117 studies involving inhibitors of cruzain and rhodesain, being thiosemicarbazones, semicarbazones, N-acylhydrazones, thiazoles-hydrazone, thiazolidinones-hydrazones, oxadiazoles, triazoles, triazines, imidazoles, peptidomimetic, and others. All references were obtained using “cruzain” or “rhodesain” and “inhibitor” as keywords in Science Direct, Bentham Science, PubMed, Espacenet, Springer, ACS Publisher, Wiley, Taylor and Francis, and MDPI (Multidisciplinary Digital Publishing Institute) databases. Finally, we highlighted all these chemical classes of molecules to provide valuable information that could be used to design new inhibitors against Chagas disease and sleeping sickness in the future.

Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivativesGuanylhydrazones have shown promising antitumor activity in preclinical tumor models in several studies.In this study, we aimed at evaluating the cytotoxic eff ect of a series of synthetic guanylhydrazones. Diff erent human tumor cell lines, by including HCT-8 (colon carcinoma), MDA-MB-435 (melanoma) and SF-295 (glioblastoma) were continuous exposed to guanylhydrazone derivatives for 72 hours and growth inhibition of tumor cell lines and macrophages J774 was measured using tetrazolium salt (MTT) assay. Compounds 7, 11, 16 and 17 showed strong cytotoxic activity with IC 50 values lower than 10 μmol L -1 against four tumor cell lines. Among them, 7 was less toxic to non-tumor cells. Finally, obtained data suggest that guanylhydrazones may be regarded as potential lead compounds for the design of novel anticancer agents.

Background: Computer-Aided Drug Design (CADD) techniques have garnered a great deal of attention in academia and industry because of their great versatility, low costs, possibilities of cost reduction in in vitro screening and in the development of synthetic steps; these techniques are compared with high-throughput screening, in particular for candidate drugs. The secondary metabolism of plants and other organisms provide substantial amounts of new chemical structures, many of which have numerous biological and pharmacological properties for virtually every existing disease, including cancer. In oncology, compounds such as vimblastine, vincristine, taxol, podophyllotoxin, captothecin and cytarabine are examples of how important natural products enhance the cancer-fighting therapeutic arsenal. Objective: In this context, this review presents an update of Ligand-Based Drug Design and Structure-Based Drug Design techniques applied to flavonoids, alkaloids and coumarins in the search of new compounds or fragments that can be used in oncology. Methods: A systematical search using various databases was performed. The search was limited to articles published in the last 10 years. Conclusion: The great diversity of chemical structures (coumarin, flavonoids and alkaloids) with cancer properties, associated with infinite synthetic possibilities for obtaining analogous compounds, creates a huge chemical environment with potential to be explored, and creates a major difficulty, for screening studies to select compounds with more promising activity for a selected target. CADD techniques appear to be the least expensive and most efficient alternatives to perform virtual screening studies, aiming to selected compounds with better activity profiles and better “drugability”.

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.