Medicinal Chemistry in South America: From Tropical Diseases to Cancers and Other Major Afflictions

According to the Centers for Disease Control and Prevention, the 10 leading causes of death in the United States during 2019 in decreasing order are heart disease, malignant neoplasms, unintentional injury, respiratory diseases, cerebrovascular diseases, Alzheimer’s disease, diabetes, nephritis, influenza and pneumonia, and suicide (https://wisqars-viz.cdc.gov:8006/lcd/home). In Brazil, as a representative country in South America, the leading causes of death during 2019 in decreasing order are heart disease, stroke, lower respiratory infections, COPD, interpersonal violence, diabetes, Alzheimer’s disease, road injuries, chronic kidney diseases, and cirrhosis (http://www.healthdata.org/brazil). The data for Argentina (http://www.healthdata.org/argentina), Chile (http://www.healthdata.org/chile), and Uruguay (http://www.healthdata.org/uruguay) are comparable albeit not identical. With all these countries, there are significant overlaps of causes of mortality and the associated morbidities of each disease with those in the United States. However, in South American countries, there is the added burden of neglected diseases that are in large part tropical infectious diseases including bacterial diseases such as tuberculosis, viral diseases such as yellow fever and dengue fever, as well as parasitic diseases including malaria, chagas fever, and other trypanosomiases and schistosomiasis. All are diseases of the nightmare world. This collection of 15 published articles from South America has been selected because the science is excellent but, additionally, because the first author and/or communicating authors carried out research in one of the countries of South America. Of course, there are other articles with coauthorship from the region but led by groups north of the Equator. These are not included for geographic and not scientific reasons.

The 15 articles span global diseases such as cancers and CNS diseases, but the principal focus is the infectious diseases of South America, where current therapies are far from ideal and new APIs are required to meet clinical need. In this report, papers focused on infectious diseases are summarized first, followed by those concerned with cancers and finally other papers.

Chagas Disease

Chagas disease is a serious infection in Latin America and elsewhere caused by the flagellate protozoan Trypanosoma cruzi (https://www.cdc.gov/parasites/chagas/index.html; https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)), a parasite carried by insects such as the kissing bug, a sweet name for a vile insect, Rhodnius prolixus, that transmits T. cruzi usually at night, after feasting on blood, as the victim sleeps (Figure 1). The current therapies for treating Chagas disease in its early stages include treatment with benznidazole or nifurtimox, medicines that have significant undesirable side effects and are less effective as therapeutics during the later chronic stages of the infection, when heart abnormalities, among other morbidities, become more pronounced. The World Health Organization estimated that 6–7 million people mostly in South America have Chagas disease and 30% of patients chronically infected develop heart alterations (https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)).

Figure 1.

(Left) Rhodnius prolixus, the kissing bug, preparing to feed and thereby potentially infecting a patient. Credit: Erwin Huebner. (Right) Photomicrograph of Giemsa-stained blood showing Trypanosoma cruzi protozoan. Image is from the Public Health Image Library of the Centers for Disease Control and Prevention. Public Domain.

Cordeiro, Bruder, and co-workers have reported the synthesis of 26 analogues of epiandrosterone by 3β-esterification, 3β-etherification, 3β-alkanesulfonylation, and/or 16α-bromination and their assay against both human and Trypanosoma cruzi glucose-6-phosphate dehydrogenase (DOI: 10.1021/acsmedchemlett.0c00106). These enzymes are major producers of dihydronicotinamide adenine dinucleotide phosphate. For the parasite, this enzyme is critically important in its defense mechanism against the host oxidative attack on the parasite. Of the 26 steroids synthesized, 17 showed higher activities against T. cruzi glucose-6-phosphate dehydrogenase than the human enzyme and several such steroids were able to kill intracellular T. cruzi amastigotes, the parasitic phase which occurs during the chronic stage of the disease. While these are preliminary results and there are probable toxicity issues with the bromo-steroids, the enzyme selectivity and potential therapeutic application in patients with the advanced disease are noteworthy for further investigations.

During infection by R. prolixus, the parasite is released into the human’s blood or via mucosal membranes including the lips and eyelids at the trypomastigotes (Tps) stage, which then infect different host cells and transform into the amastigote stage (Am). In the chronic phase of the disease, the parasite Ams localize in the heart and skeletal muscles. Motran and co-workers have reported studies on the viability of growth of both T. cruzi Tps in culture medium and whole blood and Ams in bone-marrow macrophages in the presence of 3-hydroxykynurenine (3-HK), a catabolite of tryptophan. They showed that 3-HK was active against both Tps and Am at concentrations at which mammalian cell toxicity was low. Although Ams were more sensitive than Tps, both showed dose and time dependent susceptibilities to 3-HK with the parasite mitochondria and nuclei being the likely targets with a trypanocidal mechanism that may involve intraparasite superoxide and/or peroxide generation (DOI: 10.1021/acsmedchemlett.7b00169).

Furlan and co-workers have applied dynamic combinatorial chemistry to identify high affinity ligands for the T. cruzi target bromodomain-containing protein TcBDF3. Such acetyl-lysine binding proteins are associated with chromatin and nuclear acetyltransferases and are critically important for the viability and growth of the parasite. A focused recombinant protein templated dynamic library was prepared from the reversible condensation reactions of five aldehydes and d-glucose with acyl hydrazines (benzoyl, isonicotinoyl, 2-furancarbonyl, and 2-thiophenyl). These studies, along with parallel experimentation with a TcBDF3 mutant unable to bind acetyl lysine ligands, were consistent with the vanillin hydrazone of 2-thiophenylcarbonylhydrazine being bound within the hydrophobic pocket of TcBDF3. This acyl-hydrazone showed trypanocidal effects against Tps and Ams as well as at the epimastigote stage from R. prolixus but was of low toxicity to Vero cells (DOI: 10.1021/acsmedchemlett.8b00247). It is possible that hydrazone mimetics may be more active against TcBDF3 and provide novel therapeutics.

Trypanosoma brucei, the protozoan parasite responsible for African sleeping sickness, is carried by tsetse flies, genus Glossina. Silva, Gelb, and co-workers have introduced novel imidazo-pyridines and -pyrimidines as antitrypanosomal agents against T. brucei and T. cruzi, although the mode of action has yet to be established. Heterocyclization and acyl coupling reactions were used to synthesize 22 urea and amide derivatives of imidazo[1,2-a]pyridin-7-amine and -7-amide as well as imidazo-pyrimidine analogues. These showed in vitro activities against T. cruzi (IC₅₀ = 0.09 to >20 μM) and T. brucei (IC₅₀ = 0.02 to >20 μM) with the ureas having superior activities to the amides (Table 1 in the paper also has IC₉₀ values which are mislabeled as IC₅₀ values). The optimum compounds were not toxic against human lymphocytes CRL-8155 and hepatocytes HepG2 and demonstrated excellent metabolic stability, PK properties and in vivo plasma exposure in mice. The urea derivative 1 showed parasite inhibition in the murine model comparable with benznidazole and is an excellent lead for further optimization (DOI: 10.1021/acsmedchemlett.7b00202).

Schistosomiasis

Schistosomiasis or bilharzia is a widespread serious tropical disease in South America, Africa, the Caribbean, and elsewhere and is linked to poverty, poor access to fresh water, and inadequate healthcare. It is mediated by flatworms most commonly Schistosoma mansoni, S. hematobium, and S. japonicum and carried by freshwater snails of the genus Bulinus (Figure 2). There are no vaccines against the disease, and treatment with Praziquantel is not effective at the juvenile worm stage and they may develop resistance due to its high usage. Current levels of global infections are about 240 million (https://www.who.int/health-topics/schistosomiasis#tab=tab_1).

Figure 2.

(Left) Photomicrograph of a male S. mansoni. (Right) Photomicrograph of a human liver biopsy showing a clay pipe stem fibrosis due to schistosome eggs. Images are from the Public Health Image Library of the Centers for Disease Control and Prevention. Public Domain.

Silva-Junior, Andrade, and co-workers report the application of QSAR-virtual screening of potential inhibitors of S. mansoni thioredoxin glutathione reductase, a key enzyme involved in protecting the parasite against oxidative stress. This study led to the identification of a small library, which was assayed against the parasite using high-content screening microscopy, and two compounds, [(isoxazolyl)-vinyl]pyridine 2 and benzothiazole derivative 3, were shown to be comparable with Praziquantel with parasite half-maximal motility concentrations (DOI: 10.1021/acs.jmedchem.5b02038). It is possible that analogues of these novel lead structures may show enhanced inhibition of the parasite reductase particularly with the availability of X-ray crystallographic studies of the enzyme and use of CADD.

Malaria

Malaria is a major cause of morbidity and mortality globally in the tropics caused by Plasmodium falciparum and related single-celled parasites (Figure 3). It is transmitted by infected mosquitos of the Anopheles genus including A. gambiae. The parasite’s life cycle is complex with many target opportunities for treatment. However, the emergence of parasite resistance against many classes of antimalarial drugs as well as resistance among Anopheles toward some insecticides are serious global threats. The World Health Organization estimated that malaria infected 229 million people in 2019 with 409 000 deaths (https://www.who.int/news-room/fact-sheets/detail/malaria).

Figure 3.

(Left) An avidly feeding female A. stephensi mosquito. (Right) Photomicrograph of placental tissue showing erythrocytes infected with P. falciparum. Images are from the Public Health Image Library of the Centers for Disease Control and Prevention. Public Domain.

Correia, Guido and colleagues have reported the discovery of derivatives of marinoquinoline (3H-pyrrolo[2,3-c]quinoline) using parallel synthesis, SAR studies and CADD (DOI: 10.1021/acs.jmedchem.8b00143). The lead compound in this study marinoquinoline 4, showed excellent selectivity against P. falciparum compared with human hepatic cells (>6410) with in vitro nanomolar activity against the resistant erythrocytic form of the parasite. Additionally, the lead marinoquinoline was fast acting and additive with artesunate. The mode of action is unclear and probably not associated with hemozoin metabolism but may involve inhibition of dihydroorotate dehydrogenase, cytochrome bc1 complex, phosphatidylinositol 4-OH kinase, or cyclic amine resistance locus since the marinoquinolines are active against both the liver and blood stages. Further investigations may lead to analogues with enhanced in vivo activities particularly in drug combinations.

Based on previous studies, Serra and co-workers have undertaken the synthesis of eight cyclo-hexapeptides and one cyclo-pentapeptide containing one, two or three N-methyl-glycine residues using solid-phase peptide synthesis on 2-chlorotrityl chloride resin, HBTU or HCTU-mediated couplings, TFA cleavage and macrocyclization in solution using HBTU or HATU or on resin with subsequent TFA cleavage (DOI: 10.1021/acsmedchemlett.8b00543). Several of the cyclopeptides showed sub-nanomolar growth-inhibition activities against P. falciparum K1 and P. falciparum 3D7, had comparable killing profiles to Artesunate, Chloroquine, Pyrimethamine, and Atovaquone, albeit generally at lower efficiencies, and were active against the liver stage of the parasite at submicromolar EC₅₀’s. The compounds were of very low cytotoxicity against murine macrophage or HepG2 cells, with selectivity indices as high as 10⁷ and 10⁶ respectively. Two cyclo-hexapeptides were efficacious in vivo in murine models. Further studies are needed with these intriguing leads to determine mode of action and to further enhance in vivo efficacy.

Tuberculosis

Tuberculosis (TB) is the world’s leading infectious disease with over 10 M new infections each year and 1.5 million mortalities (https://www.who.int/health-topics/tuberculosis#tab=tab_1). This respiratory infection is caused by the bacterium Mycobacterium tuberculosis, a member of the Mycobacteriaceae (Figure 4). Although Asian and African countries are the major centers with significant levels of TB, infection levels in South America are rising particularly among those incarcerated (DOI: 10.1016/S0140-6736(20)32578-2). Current therapies for treating TB use combinations of the antibiotics isoniazid, rifampin, ethambutol and pyrazinamide for 6–9 months with subsequent possible use of alternatives including fluoroquinolones, aminoglycosides, d-cycloserine, or Bedaquiline. However, such treatments are nonideal on account of emerging multidrug resistance, reduced drug efficacy during the latent phase of M. tuberculosis, inadequate patient compliance, given the prolonged therapies schedules, and side effects and toxicities.

Figure 4.

(Left) Digitally colorized SEM image of M. tuberculosis. (Right) Anteroposterior chest X-ray of a patient with tuberculosis. Images are from the Public Health Image Library of the Centers for Disease Control and Prevention. Public Domain.

Following earlier studies on heterocyclic N-oxides, Pavan, Leandro dos Santos, and colleagues have reported the synthesis and biological evaluation of 3 furoxan-N-oxide, 10 benzofuroxan-N-oxide, and 9 quinoxaline-N,N′-dioxide derivatives all bearing isonicotinoyl-hydrazone or substituted benzoyl-hydrazone groups (DOI: 10.1021/acs.jmedchem.7b01332). All were assayed against M. tuberculosis strain H37Rv and showed MIC₉₀ values of 0.40 to >62 μM. In addition, N-oxides with MIC values under 10 μM were assayed in the MRC-5 human lung fibroblast cell line. The benzo-[c][1,2,5]oxadiazole 1-oxide derivative 5, which was noncytotoxic with SI ≥ 10, was assayed against the dormant form of M. tuberculosis strain H37Rv in the J774A.1 macrophage cell line. Based on further inhibition studies with six monoresistant strains of M. tuberculosis and ADMT studies, acyl-hydrazone 5 was examined further in mode of action studies and for its efficacy in vivo. This lead compound showed effects consistent with it being an inhibitor of translation initiation. In BALB/c mice, the orally administered compound showed no significant toxicity and total suppression of growth of M. tuberculosis in lung tissue. Clearly, the efficacy of the lead compound against actively growing and dormant M. tuberculosis as well as the preliminary in vivo studies are favorable auspices for further SAR optimization.

Santos, Machado, and co-workers, following earlier studies on quinoline derivatives active against M. tuberculosis, report the synthesis of a range of 2-methyl-6-R¹-2-(quinolin-4-yloxy)acetamides (R¹ = H, OMe) N-functionalized with substituted phenyl groups, benzyl or naphthyl (R²) 6 by the simple etherification reactions from the corresponding 4-hydroxyquinolines with 2-bromo-N-aryl(benzyl)acetamides (DOI: 10.1021/acsmedchemlett.5b00324). All were compared with the standard TB drug isoniazid in an in vivo assay against M. tuberculosis strain H₃₇Rv as well as against three clinical resistant isolates: RS-036 and RS-032, both isoniazid monoresistant, and PE-003, which is multidrug resistant against isoniazid, rifampin, etambutol, and streptomycin. Additionally, selected compounds were found to be inactive against Eschericia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii. Analysis of cytotoxicity assays against RAW 264.7 murine macrophage cells as well with Vero and HaCat cells, studies on intracellular activities, physicochemical properties and metabolic stability, CYP450 inhibition, and assays of cardiotoxicities in a zebrafish model led to the selection of five leads with comparable activities to rifampin. As such, these optimum 2-(quinolin-4-yloxy)acetamides are physicochemically suitable to transverse host and parasite cell walls and thereby to inhibit M. tuberculosis inside macrophages. They are excellent leads for further optimization and development.

Candida auris Infections

Candida auris is a very dangerous yeast pathogen that is multidrug resistant and the cause of invasive infections with high levels of mortality (30–60%) particularly among patients who are immunocompromised and suffering from other comorbidities. Many infections occur in hospitals and are often associated with invasive procedures such as catheterization. C. auris can infect the bloodstream, CNS, and organs such as the liver and kidneys, lungs, and eyes (https://www.cdc.gov/fungal/candida-auris/candida-auris-qanda.html). Since this pathogen is invariably resistant to Fluconazole and other azoles, treatment regimens involve echinocandins and, subsequently, amphotericin B, a drug with significant serious side effects (https://en.wikipedia.org/wiki/Amphotericin_B#Side_effects).

Ishida, Stefani and colleagues have reported the synthesis of 25 (4S,5S)-aryl-oxazolines from the cyclo-condensation reactions of functionalized salicylic and 1-hydroxy-2-naphthoic acids with L-threonine derivatives mediated with EDC, HOBt and NMM followed by thionyl chloride, thionyl bromide or Deoxofluor (DOI: 10.1021/acsmedchemlett.0c00449). The reader should note that there are errors in this paper in the depictions of absolute stereochemistries of the oxazolines in Figure 1 and most of the Supporting Information. These were bioassayed against susceptible and Fluconazole-resistant Candida species including the multidrug-resistant C. tropicalis ATCC 200956. In general, the 1-hydroxy-2-naphthyl oxazolidines (MIC geometric media from 0.04 to 0.7 μM) were more active than the 2-hydroxyphenyl oxazolidines (MIC geometric media from 0.14 to 2.1 μM) and comparable to caspofungin (0.40 μM) and amphotericin B (0.08 μM). Some oxazolidines from both series showed hepatotoxicity toward HepG2 cells but none mediated significant levels of hemolysis of red blood cells. The lead structures from these studies were the aryl-oxazolines 7–9. Both aryl-oxazolines 7 and 9 were active against the clinical isolates C. auris CBS 10913, C. auris CBS-12766, C. duobushemeulonii CBS 7799, and C. duobushemeulonii CBS 10004 (MIC 0.03 to 2.0 μM). Finally, several aryl-oxazolines including 7 and 9 inhibited the growth of Cryptococcus neoformans and C. gattii (MIC 0.25 to 16 μM) but less effective against Aspergillus fumigatus and A. niger. Aryl-oxazolines are potentially useful lead structures for further optimization for the treatment of superficial and invasive C. auris infections.

Cancer

This section of the editorial covers medicinal chemistry investigations of inhibitors of histone deacylases, MAP kinase, and thymidine phosphorylase, all established targets for the invention and development of cancer therapeutics, among other diseases.

Inhibitors of histone deacetylases (HDACs) are potentially useful cancer therapeutics. Fraga and co-workers have described the synthesis of six meta-acylhydrazones 10 and eight para-isomers 11 and 12 and their in vitro assays of dual HDAC-6 and −8 inhibitors (DOI: 10.1021/acs.jmedchem.5b01525). HDAC-6 inhibitors are notable for affecting cell invasion, proliferation, and metastasis as well as upregulating death receptors, whereas HDAC-8 inhibitors reduce proliferation and bring about apoptosis and cell cycle arrest. In contrast to trichostatin A, acylhydrazones 10–12 were selective inhibitors of HDAC-6 and -8 but not HDAC-1 and -2. Acylhydrazone hydroxamic acids 11 (R = H, Me; X = NHOH) were of comparable activities to trichostatin A, within experimental error, against HDAC-6 and -8 (IC₅₀ = 0.015–0.23 μM). Incorporation of an additional methyl group (R²) enhanced inhibition of HDAC-8 but decreased that of HDAC-6. SAR was analyzed by enzyme crystal structure based modeling and selected compounds tested for antiproliferative activities. Among the best inhibitors, acylhydrazones 11 (R¹ = H; R² = H; X = NHOH) and 12 (R¹ = H; R² = Me; X = NHOH), respectively, mediated cell cycle arrest and death of HepG2 cells, and inhibited caspase 3/7 activation and induced apoptosis.

Since p38 mitogen-activated protein kinase (MAPK) is upregulated with cellular stress and is involved in cell differentiation, apoptosis, and autophagy, its α-form is an excellent target for inhibitor design as cancer therapeutics. Laufer, Barreiro, and co-workers have reported the design of analogues of the known potent highly selective inhibitor skepinone-L with retention of the hinge domain but variation in the R-spine region to enhance metabolic stability and residence time in the kinase (DOI: 10.1021/acs.jmedchem.0c00508). Novel analogues 13a–13d of known related dibenzosuberones 13e and 13f were synthesized using Buchwald–Hartwig amination as the key step. Bioevaluations of analogues 13a and 13d in the ADP-glo and NanoBRET cellular MAPK inhibitor assays showed these compounds to have nanomolar activities and these activities were sequentially lower with thiophene 13b and selenophene 13c. In the human blood TNF-α assay, analogue 13a was comparable to the known standards 13e and 13f. All new analogues had high target resident times significantly greater than the references and the order of metabolic stability toward human liver microsomes was 13a > 13e > 13d. Extension of the reported CADD studies to further derivatization of acyl-hydrazone 13a may provide compounds to progress to in vivo assays and toxicological studies.

Basso, Machado, and colleagues reported studies of the design, synthesis, and bioassay of a series of 2,4-pyrimidinediones 14 as inhibitors of human thymidine phosphorylase (DOI: 10.1021/acs.jmedchem.8b01305). This enzyme enhances cellular levels of pyrimidine nucleotides necessary for DNA replication and repair. It is upregulated in tumors, and its inhibition is associated with suppression of angiogenesis, cancer growth and metathesis. By consideration of the likely enzyme-mediated S_N2 or S_N1 or mixed mechanism pathway for the reversible phosphorylation of thymidine with phosphate to provide thymine and 2-deoxy-α-d-ribofuranosyl phosphate, the authors considered that the 2,4-pyrimidinedione 14 would mimic the transition state with the protonated amine resembling the 2-deoxy-α-d-ribofuranosyl carbenium ion, the heterocycle the thymine and the R² or linked R¹–R² groups acting as sugar surrogates. The pyrimidinediones 14 were synthesized from 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione by sequential ring halogenation and displacement by amine R¹R²NH. They inhibited human thymidine phosphorylase in vitro (IC₅₀ = 0.12 to >100 μM) with the most effective noncompetitive inhibitor being 14 (X = I, R¹ = H, R² = CH(CH₂OH)₂), which was further examined by molecular docking studies. This inhibitor was of low mammalian cell toxicity, no CYP450 liability, moderate rates of metabolism and of efficacy in reducing the growth of the human glioma U-87 MG cells in BALB/c mice xenografts comparable to Temozolomide.

Other Manuscripts

Brain acetylcholinesterase inhibitors alleviate the progression of Alzheimer’s disease (AD) by enhancing acetylcholine levels but also by reducing β-amyloid peptoid deposition. Inhibition of the related butyrylcholinesterase is also associated with therapeutic benefits to patients. The analgesic capsaicin exhibits antioxidant properties including reduction of protein oxidation, oxidative stress and neuroinflammation with AD. Inestrosa, Colletier, Renard, Muñoz-Torrero, and colleagues have reported the synthesis and bioassays of dual agents functionalized with both antioxidant capsaicin and cholinesterase inhibitor huprine groups 15 and 16 linked by a variable XY spacer using amide coupling, ruthenium catalyzed crossed metathesis and a Huisgen Sharpless azide and acetylene cycloaddition (DOI: 10.1021/acs.jmedchem.0c01775). All the adducts 15 and 16 showed antioxidant activities comparable to capsaicin and retained the acetyl- and butyryl-cholinesterase inhibition of huprine with 15 [XY = NH(CH₂)₆] being of greater potency than huprine and 16 having excellent activities against acetyl- and butyryl-cholinesterase (1.06 and 7.3 nM, respectively). Kinetic studies of inhibition by 15 [XY = NH(CH₂)₅] and X-ray crystallographic studies showed the (7S,11S)-huprine of several complexes were bound in the catalytic anionic site (CAS), whereas the capsaicin group was bound at the peripheral anionic site (PAS). Adducts 15 [XY = NH(CH₂)₆] and 16 passed through the blood-brain barrier in C57BL6 mice and the second compound significantly improved learning and memory in mouse models of AD from a range of behavioral studies and subsequent biopsies.

Schwartz and co-workers have reported the fractionation by RP-HPLC of the venom of Tityus obscurus, the Amazonian black scorpion, with bioassay of fraction as trypsin inhibitors (DOI: 10.1021/acs.jmedchem.0c00686). This led to the identification of ToPI1 as the only active inhibitor, and the amino acid sequence was determined by MALDI in-source decay and from the cDNA library. This 33 amino acid peptide, which has three disulfide bonds and is C-terminus amidated, was additionally synthesized by SPPS, as was the peptide with Lys²¹ replaced by Ala²¹. Both native and synthetic ToPI1 inhibited trypsin in a 1:1 stoichiometry with the ToPI1 Lys³² in the trypsin S1 pocket. The nature of the complexation was determined using surface plasmon resonance, circular dichroism spectroscopy, and X-ray crystallography. Intriguingly, the interaction of synthetic ToPI1 with trypsin resulted in Ser³³ cleavage and macrocyclization of the toxin, via a peptide bond formation between Ile¹ and Lys³², providing a structure reminiscent of plant cyclotides such as MCoTI-II. Both ToPI1 and its cyclic des-Ser³³ derivative may prove to be useful probes in the study of diverse morbidities.

We very much hope that you will find this selection of top-flight publications from South America informative, uplifting, and enjoyable and that you will join us in congratulating the splendid authors in Argentina, Brazil, Chile, and Uruguay for their contributions to medicinal chemistry and associated disciplines. In many cases, the South American authors have copublished with authors from diverse countries north of the Equator. These Latin American institutes are in many beautiful cities including Araraquara, Brasília, Campinas, Caxias do Sul, Córdoba, Goiânia, Montevideo, Porto Alegre, Punta Arenas, Rio de Janeiro, Santiago, and São Paulo. Perhaps, readers would consider visiting several of these delightful destinations to further discuss chemistry, experience the lifestyle, and see these spectacular destinations.

We thank these authors of the cited papers for their contributions to drug discovery and development and all others who have contributed to maintaining the scientific excellence of the Journal of Medicinal Chemistry and ACS Medicinal Chemistry Letters. We additionally thank Professor Matthew J. Fuchter (Imperial College London) for assistance in the selection of articles and Thomas Mies and Laura Medve for proofreading the manuscript.

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

Author Status

^† Anthony G. M. Barrett is also a resident of Rio de Janeiro, Brazil.