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Nowadays, boron-containing compounds have gained researchers’ attention because of the wide versatility and applicability of this element in both organic and medicinal chemistry. Since its discovery, its use in medicinal chemistry was neglected because of its possible toxic effects. However, in the past years, boron-containing compounds did not show such effects, and some drugs have already been approved by the Food and Drug Administration to treat diseases, including cancer, infections, and inflammation. Several boroncontaining compounds are used in organic and medicinal chemistry, either as a reagent or therapeutic agent. The chemical properties of this element make its use possible in organic synthesis as a reducing agent and catalyst, mainly in cross-coupling reactions. Among boroncontaining compounds, boranes, azaborines, benzoxaborole, boronic acid, and boron derivatives are most commonly described. This review article discusses the main properties of boron-containing compounds, their preparation by organic synthesis, as well as their applications in organic synthesis and medicinal chemistry fields, developing new perspectives for further investigations.

Sickle cell anemia (SCA) is a hematological genetic disorder caused by a mutation in the gene of the β-globin. Pharmacological treatments will continue to be an important approach, including the strategy to induce fetal hemoglobin (HbF). Here, we analyzed the articles described in the literature regarding the drug discovery of HbF inducers. The main approaches for such strategy will be discussed, highlighting those most promising. The comprehension of the mechanisms involved in the β-globin regulation is the main key to design new drugs to induce HbF. Among the strategies, gamma-globin regulation by epigenetic enzymes seems to be a promising approach to be pursued, although the comprehension of the selectivity role for those new drugs is crucial to reduce adverse effects. The low druggability of transcription factors and their vital role in embryonic human development are critical points that should be taken in account for drug design. The guanylate cyclase and the NO/cGMP signaling pathway seem to be promising not only for HbF induction, but also for the protective effects in the cardiovascular system. The association of drugs acting through different mechanisms to induce HbF seems to be promising for the discovery of new drugs.

Made available in DSpace on 2021-06-25T11:11:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-20 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC90 values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis. School of Pharmaceutical Sciences São Paulo State University (UNESP), Araraquara Jaú Highway KM 01 Institute of Chemistry São Paulo State University (UNESP), Francisco Degni Street 55 School of Pharmaceutical Sciences São Paulo State University (UNESP), Araraquara Jaú Highway KM 01 Institute of Chemistry São Paulo State University (UNESP), Francisco Degni Street 55 FAPESP: 2016/09502-7 FAPESP: 2018/00163-0 FAPESP: 2018/11079-0 FAPESP: 2018/17739-2 FAPESP: 2018/21778-3 FAPESP: 2018/24783-8 CNPq: 404181/2019-8 CNPq: 429139/2018-7

Made available in DSpace on 2020-12-12T01:23:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Optical Society Universidade Estadual Paulista Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) National Institutes of Health Resveratrol (RVT) derivatives (10a-i) were designed, synthesized, and evaluated for their potential as gamma-globin inducers in treating Sickle Cell Disease (SCD) symptoms. All compounds were able to release NO at different levels ranging from 0 to 26.3%, while RVT did not demonstrate this effect. In vivo, the antinociceptive effect was characterized using an acetic acid-induced abdominal contortion model. All compounds exhibited different levels of protection, ranging from 5.9 to 37.3%; the compound 10a was the most potent among the series. At concentrations between 3.13 and 12.5 µM, the derivative 10a resulted in a reduction of 41.1–64.3% in the TNF-α levels in the supernatants of macrophages that were previously LPS-stimulated. This inhibitory effect was higher than that of RVT used as the control. In addition, the compound 10a and RVT induced double the production of the gamma-globin chains (γG + γA), compared to the vehicle, using CD34+ cells. Compound 10a also did not induce membrane perturbation and it was not mutagenic in the in vivo assay. Thus, compound 10a emerged as a new prototype of the gamma-globin-inducer group with additional analgesic and anti-inflammatory activities and proving to be a useful alternative to treat SCD symptoms. São Paulo State University (UNESP) School of Pharmaceutical Sciences University of Campinas (UNICAMP) Hematology and Hemotherapy Center Weill Cornell Medical College Department of Physiology and Biophysics São Paulo State University (UNESP) School of Pharmaceutical Sciences FAPESP: 2012/50359-2 FAPESP: 2014/00984-3 CNPq: 304731/2017-0 National Institutes of Health: GM21342

Sickle Cell Disease (SCD) is an inherited disorder of red blood cells that is caused by a single mutation in the β -globin gene. The disease, which afflicts millions of patients worldwide mainly in low income countries, is characterized by high morbidity, mortality and low life expectancy. The new pharmacological and non-pharmacological strategies for SCD is urgent in order to promote treatments able to reduce patient’s suffering and improve their quality of life. Since the FDA approval of HU in 1998, there have been few advances in discovering new drugs; however, in the last three years voxelotor, crizanlizumab, and glutamine have been approved as new therapeutic alternatives. In addition, new promising compounds have been described to treat the main SCD symptoms. Herein, focusing on drug discovery, we discuss new strategies to treat SCD that have been carried out in the last ten years to discover new, safe, and effective treatments. Moreover, non-pharmacological approaches, including red blood cell exchange, gene therapy and hematopoietic stem cell transplantation will be presented.

Heterocyclic N-oxides have emerged as promising agents against a number of diseases and disorders, especially infectious diseases. This review analyzes the emergence and development of this scaffold in the medicinal chemistry, focusing mainly on the discovery of new heterocyclic N-oxide compounds with potent activity against tuberculosis, malaria and neglected tropical diseases (i.e. leishmaniasis and Chagas disease). A number of heterocyclic N-oxides are described herein, nevertheless, the following chemical classes deserve to be highlighted due to a large number of reports in the literature about their promising pharmacological effects: furoxan, benzofuroxan, quinoxaline 1,4-di-N-oxide, indolone N-oxide and benzimidazole N-oxide. In order to describe those most promising compounds, we included in this review only those most biologically active heterocyclic Noxide published since 2000.

Leishmaniasis is a neglected tropical disease, endemic in 98 countries and with more than 350 million people with risk to be sick. From 2001 to 2014, leishmanisis caused 797,849 of new cases of cutaneous and mucosal forms. Moreover, only in 2014, visceral leishmaniasis was detected in 3,624 american people, being Brazil responsible for 95% of this cases. Leishmania are protozoan parasites who lives in the midgut and foregut of the female sandfly of the genera Phlebotomus (Africa, Asia and Europe) and Lutzomyia (Central and South America), which is the sole vector responsible for transmitting this disease. Even though the knowledge in molecular biology and biochemistry about the parasite has increased, the first and second choice drugs for the treatment are still obsolete and with high toxicity in a long-term treatment. In this work, we describe the synthesis, leishmanicidal activity of furoxan derivatives against Leishmania amazonensis and Leishmania infantum and their bioavailability prediction. The compounds were synthesized from furoxan derivatives and aminoguanidine hydrochloride to give four new molecules in good global yields ranging from 30-60%. Compounds I-IV were characterized by analytical methods including NMR, infrared and mass spectrometry. The novel compounds were evaluated in two different species of Leishmania: Leishmania amazonensis and Leishmania infantum. The compounds were less cytotoxic than pentamidine. It is important to highlight the compound III, which presented a CC50 in macrophages of 1095.52 µM, which is considerably higher than pentamidine (35.69 µM), what means that its cytotoxicity is remarkably lower than the second line drug used in leishmaniasis treatment. In the evaluation against promatigotes forms, all compounds have demonstrated IC50 values superior to that of pentamidin against Leishmania amazonensis and a low IC50 values compared with pentamidine against Leishmania infantum. Compound II presented the most promissor IC50 against Leishmania infantum strain with a value of 8.87 µM, while pentamidine presents an IC50 value of 67.71 µM. For amastigote form, only two compounds with selective index superior to 15 (compounds I and III) were selected to be evaluated, and both of them presented an IC50 higher than pentamidine. The bioavailability prediction has demonstrated that all compounds are in agreement with the Lipinski rule, and their intestinal absorption was around 70%. All these data allow us to conclude that the compounds were more effective against the promastigote forms of Leishmania infantum, which is responsible for the visceral form of leishmaniasis. In addition to their important and significant low cytotoxicity, these compounds may be a future alternative to leishmaniasis treatment.

Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine, however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.

Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1).

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs.