Medicinal Chemistry Approaches Research Articles

AR DNA binding domain inhibitors to treat AR splice variant-driven prostate cancer.

293 Background: Nearly all prostate cancer (PC) cells depend on androgen receptor (AR) signaling for growth. Resistance to novel PC drugs like abiraterone and enzalutamide appears to occur through ligand-independent AR signaling, often by expression of AR splice variants (ARv’s) that lack the ligand binding domain (LBD). Thus, drugs that inhibit AR activity via domains other than the LBD may provide a way to inhibit the growth of drug-resistant PC. We discovered the first non-competitive, ligand-independent AR inhibitor, pyrvinium pamoate (PP), which functions by interacting with the DNA-binding domain (DBD) and preventing the recruitment of RNA polymerase II to transcription start sites. PP inhibits AR activity with low nanomolar potency and functions synergistically with competitive antagonists. Here, we undertook experiments to learn more about PP’s mechanism of action and developed an orally available derivative for translation to human studies. Methods: AR immunoprecipitation (IP) followed by mass spec sequencing was used to identify proteins that differentially bind to AR in the presence of PP. Additionally, RNA-seq was used to identify pathways affected by PP treatment. Functional studies of hits were conducted using over-expression and knock down in relevant PC cell lines. PP derivatives were developed through a medicinal chemistry approach. Lead compounds were tested in a battery of assays to determine potency in cultured cells and in vivo, as well as their solubility and pharmicokinetics. Results: RNA-seq results suggest that AR and hormone pathways are the primary target of PP in PC cells but that the splicing machinery is also be affected. Mass spec results also demonstrate that PP affects the interaction between AR and splicing machinery, as well as many transcription and translation-related proteins. Medicinal chemistry efforts led to a molecule with superior aqueous solubility, oral availability, and a half-life > 6hrs. This compound inhibited the activity of AR and ARv’s in cultured cells and in xenograft models. Conclusions: PP was the first identified AR DBD inhibitor and the development of an orally available derivative holds great promise for the treatment of ARv-driven PCs.

Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.

Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain.

Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies.

Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compounds are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their molecular target, the DNA gyrase, was identified soon after the analysis of myxobacterial self-resistance making use of the information found in the respective biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clinical setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin derivative with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their production scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent derivative exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compound is now subject to further optimization by medicinal chemistry approaches.

Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase

We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too.

Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts.

Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2). We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28days in response to 0.3mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy signaling in HUVECs raise the possibility that both cyanobacterial natural products share a common mechanism of action.

Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders.

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.

What Makes Us Smell: The Biochemistry of Body Odour and the Design of New Deodorant Ingredients.

Today, axilla odours are socially stigmatized and are targeted with deodorants and antiperspirants representing a multi-billion market. Axilla odours aren't simple byproducts of our metabolism but specifically formed by an intricate interplay between i) specific glands, ii) secreted amino acid conjugates of highly specific odorants and iii) selective enzymes present in microorganisms colonizing our skin, providing a natural 'controlled-release' mechanism. Within a multidisciplinary research project, we were able to elucidate the structure of key body odorants, isolate and characterize secreted amino acid conjugates and identify the enzymes responsible for odour release. These enzymes then served as targets for the development of specific active compounds in an almost medicinal chemistry approach, an approach rarely used in the cosmetic field so far. Here we review the key new insights into the biochemistry of human body odour formation, with some remarks on the experimental steps undertaken and hurdles encountered. The development of deodorant actives and the difficult path to market for such specifically acting cosmetic actives is discussed. The basic insights into the biochemistry also opened the way to address some questions in population genetics: Why have large proportions of Asians lost the 'ability' to form body odours? Do twins smell the same? Are our typical body odours indeed influenced by the immune system as often claimed? After addressing these questions, I'll conclude with the key remaining challenges in this field on an ecological niche that is 'anatomically very close to our heart'.

Abstract 2585: Discovery of a potent covalent mutant-selective EGFR inhibitor - the journey from high throughput screening to EGF816

Abstract Epidermal growth factor receptor (EGFR) is a validated therapeutic target for lung cancer. First and second generation EGFR inhibitors (e.g., gefitinib, erlotinib and afatinib) have revolutionized treatment paradigms of non-small cell lung cancer (NSCLC) patients with oncogenic EGFR mutations. The use of EGFR tyrosine kinase inhibitors (TKI) provides superior efficacy compared to chemotherapy in patients with EGFR L858R or exon 19 deletion tumors. However, resistance inevitably develops after 8-12 months of treatment; most commonly via a secondary T790M point mutation at the gatekeeper residue of EGFR. Furthermore, responses are hindered due to treatment intolerance in the form of rash and diarrhea that are mediated by simultaneous inhibition of wild-type (WT) EGFR at doses required for mutant EGFR suppression. To overcome these limitations, we initiated a project to identify mutant-selective EGFR inhibitors that potently inhibit both activating and T790M resistance EGFR mutations while sparing WT EGFR. In this presentation, we report our medicinal chemistry approach and optimization that led to the discovery of EGF816, a selective and potent covalent mutant-selective EGFR inhibitor with single digit nanomolar cellular target modulation on both activating and T790M resistance mutations. In addition, we will also report validated clinical efficacy data from the first patient treated with EGF816. Citation Format: Gerald Lelais, Robert Epple, Pierre-Yves Michellys, Thomas H. Marsilje, Yun Long, Matthew McNeill, Bei Chen, Wenshuo Lu, Badry Bursulaya, Michael DiDonato, Yong Jia, Shailaja Kasibhatla, Chun Li, Igor Matushansky, Steven Bender. Discovery of a potent covalent mutant-selective EGFR inhibitor - the journey from high throughput screening to EGF816. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2585. doi:10.1158/1538-7445.AM2015-2585

Abstract 4097: Small molecule mediated transcriptional derepression of E-cadherin and inhibition of epithelial to mesenchymal transition

Abstract BACKGROUND: Transcriptional repression of E-Cadherin is a hallmark of Epithelial-to-Mesenchymal Transition (EMT) and is associated with metastasis in cancer. Understanding mechanisms behind E-cadherin repression may provide important insights into the regulation of EMT and novel therapeutic strategies for cancer. In this report, we applied a medicinal chemistry approach to generate a novel EMT-reversing compound, ML327. We tested the hypothesis that ML327 activity impinges directly on the mechanism of EMT in cancer and represents a potential therapeutic agent to block or reverse EMT in vivo. METHODOLOGY/PRINCIPAL FINDINGS: We used cell based biochemical approaches to show that ML327 increases E-cadherin expression in 5 cancer cell lines and 2 non-transformed cell lines. ML327 was shown to induce global changes in histone modifications, but through a distinct mechanism than similar chemical agents such as Histone De-Acetylase (HDAC) inhibitors. Cell based assays were used to show that ML327 inhibits cell invasion, partially reverses EMT, and inhibits metastasis in vivo. We examined gene expression changes induced by ML327 within 3 hrs in the presence of cycloheximide by RNA-seq and determined a mechanistic requirement for Hepatocyte Nuclear Factor 4α (HNF4α) in ML327 activity on E-cadherin gene expression. Through direct testing, we have determined the ML327 is not a promiscuous chemical probe and that it lacks direct HDAC inhibitory and kinase inhibitory activity, however, our study is limited by the lack of identification of the direct cellular target. Significant ongoing studies are designed to address this limitation. CONCLUSIONS/SIGNIFICANCE: ML327 increases E-cadherin in cells and translate to an important biological behavior in vivo that may be exploited for therapeutic potential in cancer. Furthermore, ML327 represents a novel chemical structure for continued pharmacological optimization toward the development of novel therapeutics. ACKNOWLEDGEMENTS: This work was supported by NIH through the Molecular Library Probe Center Network (MPLCN) under grant U54MH084659 to CWL. DISCLOSURE of POTENTIAL CONFLICT of INTEREST: No potential conflicts of interest were disclosed. DISCLOSURE of CHEMICAL STRUCTURES: Chemical compounds were used in this scientific work to generate the data, and the structures of the compounds will be disclosed at the time of presentation at the meeting. Citation Format: Hanbing An, Natasha Deane, Sydney Stoops, Jing Zhu, Alex Waterson, Andries Zijlstra, Craig Lindsley, Robert Daniel Beauchamp. Small molecule mediated transcriptional derepression of E-cadherin and inhibition of epithelial to mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4097. doi:10.1158/1538-7445.AM2015-4097

The Glioblastoma Problem: Targeting by Combined Medicinal Chemistry Approaches

Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current status of clinical research on GB, a literature search was conducted in PubMed using the terms: "glioma AND trial" over a 500 day period elapsing from Jan 1, 2013 to May 15, 2014 and results of Phase I, II and III trials were reviewed. Results in the pediatric setting were included as well. It was concluded that, as in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field are not presently translated to improved patients' survival. In order to explore novel therapeutic avenues for this deadly tumour, two innovative medicinal chemistry approaches are proposed and discussed: a) Specific glioma initiating cell-radiosensitization by ATM inhibitors [1] and b) Specific glioma initiating cell-chemotherapeutic targeting by MYC inhibitors [2].

Abstract 411: Discovery and Cardioprotective Effects of the First Non-peptide Agonists of Prokineticin Receptor-1

Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

Editorial: Monitoring endogenous GPCRs: lessons for drug design.

Editorial: Monitoring endogenous GPCRs: lessons for drug design.

The process of designing and developing spliceostatin class of splicing inhibitors as payloads for antibody drug conjugates

The natural product FR901464 (1), spliceostatin C (2) and thailanstatin (3), are ultrapotent inhibitors of eukaryotic RNA splicing, via binding to the SF3b subunit of the U2 snRNA subcomplex, an essential component of the spliceosome. Manipulation of the biosynthetic genes that control production of these analogs in the bacteria have allowed us to generate sufficient material for a medicinal chemistry approach to evaluating this mechanistic class as potential payloads for antibody drug conjugates (ADCs). This oral presentation will detail some successful ways to leverage spliceostatin analogs to generate potent and efficacious ADCs for the treatment of cancer.

COMMENTARY: Pre-emptive Nutrition: Refining the Targets of Drugs Targeted to Colorectal Cancer

It is suggested that our current understanding of the role of nutrients in maintaining genomic stability might be strategically employed alongside current chemotherapy, in order to prevent the emergence of drug resistant tumors and optimize medicinal chemistry approaches.

Chikungunya virus (CHIKV) inhibitors from natural sources: a medicinal chemistry perspective.

Chikungunya virus (CHIKV) is one of the re-emerging “neglected” tropical diseases whose recent outbreak affected not only Africa and South-East Asia but also several parts of America and Europe. To date, despite its serious nature, no antivirals or vaccines were developed in order to counter this resurgent infectious disease. The recent advancement in crystallography and availability of crystal structures of certain domains of CHIKV initiates the development of anti-CHIKV agents using structure-based drug design or synthetic medicinal chemistry approach. Despite the fact that almost 50 % of the new chemical entities against several biological targets were either obtained from natural products or natural product analogues, a very humble effort was directed towards identification of novel CHIKV inhibitors from natural products. In this review, besides a brief overview on CHIKV as well as the nature as a source of medicines, we highlight the current progress and future steps towards the discovery of CHIKV inhibitors from natural products. This report could pave the road towards the design of novel semi-synthetic derivatives with enhanced anti-viral activities.Graphical

Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives

Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30–100 nM). The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9) was similar in both strains and close to that of chloroquine (IC50: 20 nM) on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10) of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8) prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the intraerythrocytic asexual stages and prevent the formation of sexual stages of the parasite.

Development of Structure‐Activity Relationships for a G protein‐Biased Agonist of the D 2 Dopamine Receptor

We previously published the discovery of a highly efficacious, functionally biased D2 dopamine receptor (D2R) agonist (MLS1547) that can selectively activate G protein signaling while blocking β-arrestin recruitment. In the interest of understanding the basis for its bias, the signaling properties of 23 MLS1547 analogs were characterized, which ranged from highly biased to unbiased. These results provided the basis for development of structure-activity relationships using pharmacophore modeling and molecular docking analyses. Subsequently, 69 additional MLS1547 analogs were tested for both β-arrestin and G protein signaling, which refined our model of the structural basis for G protein bias. We have confirmed that a hydrophobic feature, like the chloro group at C5 of MLS1547 is required for G protein-biased signaling. A hydroxyl group para to the C5 group also correlates with strong biased signaling. Replacing the 2-pyridyl group with other nitrogen heterocycles alters the nitrogen basicity, and has a more nuanced effect on bias and signaling strength. Bicyclic scaffolds afforded more potent analogs than the monocyclic scaffolds investigated. Interestingly, some analogs switched from G protein to β-arrestin bias, opening up additional, interesting avenues for understanding the mechanism of biased D2R signaling. This, along with medicinal chemistry approaches will enable a highly targeted approach for investigating D2R signaling in vivo, and may eventually broaden our understanding of pathological D2R signaling in disease states.

Target-based molecular modeling strategies for schistosomiasis drug discovery.

Schistosomiasis, a neglected tropical disease caused by worms from the class Trematoda (genus Schistosoma), is a serious chronic condition that has been reported in approximately 80 countries. Nearly 250 million people are affected worldwide, mostly in the sub-Saharan Africa. Praziquantel, the mainstay of treatment, has been used for 30 years, and cases of resistance have been reported. The purpose of this perspective is to discuss current target-based molecular modeling strategies in schistosomiasis drug discovery. Advances in the field and the role played by the integration between computational modeling and experimental validation are also discussed. Finally, recent cases of the contribution of modern approaches in computational medicinal chemistry to the field are explored.

Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.

Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

Drug design for neglected disease in Brazil.

Neglected tropical diseases (NTD) are a group of 17 diseases transmitted by virus, protozoa, helminthes and bacteria. These illnesses are responsible for millions of deaths per year, affecting mainly the poorest populations in the world. The therapeutic drugs available are obsolete, toxic, have questionable efficacy and there are reports of resistance. Therefore, the discovery of new, safe, effective and affordable active molecules is urgently needed. Considering that, the main purpose of this mini-review is to show the current scenario concerning drug design for neglected disease in Brazil. NTD are a very broad topic. Thus, we selected four infections for discussion: Chagas disease, leishmaniasis, malaria and tuberculosis. According to CNPq (National Counsel of Technological and Scientific Development) directories, there are many Brazilian groups studying these respective diseases. The papers published possess high quality and some of them, the most recent, are briefly discussed here. Medicinal chemistry approaches such as synthesis of novel series of molecules and biological activity evaluation, studies of structure-activity relationships (qualitative and quantitative), molecular modeling calculations and electrochemistry are some of the tools applied in the design of the compounds.