Gliflozins are an important class of prescription drugs used to treat type II diabetes. They reduce blood sugar levels by targeting the sodium-glucose transport protein 2 (SGLT2) and consequently inhibit glucose reabsorption in the kidney. There are currently several FDA-approved gliflozins as well as others in the pipeline to be launched in the next few years. This review describes the synthetic strategies used for manufacturing SGLT2 inhibitors on both bench and industrial scales. Moreover, the drawbacks to the strategies and the improvements made to obtain selected gliflozins and their glucose derivatives over the years are highlighted.

Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.

The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36μM, was not cytotoxic when tested on Vero cells (IC50>100μM). To complement the in vitro screening, we also studied the interaction of the test compounds with β-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.

The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.

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, e meus avós, Noemia, Maria de Lourdes e Ademar). Vocês, definitivamente, fazem parte desta minha conquista e merecem fazer parte disso. Obrigado por toda base e apoio, VOCÊS SÃO MEU ALICERCE.Á minha orientadora, Profa. Dr. Elizabeth Igne Ferreira, por todas as conversas, orientações e discussões ao longo destes seis anos. Por aceitar me orientar e "topar", sem exitar, a realizar minha proposta de Doutorado. À sua amizade, pelo seu carinho e por sempre me estender a mão quando eu precisei. Tantas coisas ocorreram ao longo destes anos que a senhora se tornou mais que uma inspiração. Serei eternamente grato, muito obrigado! À minha namorada, Mariah de Almeida Ultramari, por todo apoio e motivação nos momentos difíceis que tenho passado. Por ser muito mais do que apenas uma namorada, companheira ou amiga. O significado de suas atitudes ecoam para muito além da minha compreensão. Apesar de eu ser difícil, você sempre está lá, do meu lado e comigo. Você é mais do que um MODELO para mim! Palavras me faltam para explicar o meu carinho, sentimento e apreço por ti. Se um TE AMO fosse o suficiente para quantificar e demonstrar o momento sublime que tenho ao seu lado, esta tese seria escrita apenas com essas duas palavras. MUITO OBRIGADO POR ME MOSTRAR O QUÃO FÁCIL É SER FELIZ COM A SIMPLICIDADE DA VIDA.À família Ultramari/Oltramare, por todas as conversas descontraídas e pelo ótimo tempo que passamos juntos. Vocês fazem a diferença. Agradeço por ter sido acolhido de braços abertos.À Mariana Frojuello, pelas conversas, amizade e companheirismo ao longo deste Doutorado. Juntamente à sua família (Márcia, Tereza e Ana Maria), devo dizer que sou grato por toda ajuda que tive em "sobreviver" em São Paulo. Espero ter retribuído da mesma maneira.

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