Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains.

The emergence of multidrug-resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18-1.63 µM against Mtb H37Rv. Compounds 47-49, 51-53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 µM. In Mtb-infected macrophages, several compounds demonstrated a 1-log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1-b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin-dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1-b][1,3]oxazines and their promising potential against MDR-TB.

Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis.

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.

The use of Sulfonamide Derivatives in the Treatment of Trypanosomatid Parasites including Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp.

More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.

Hydroxymethylnitrofurazone treatment in indeterminate form of chronic Chagas disease: Reduced intensity of tissue parasitism and inflammation-A histopathological study.

Hydroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug effective in vivo during acute infections, and it has less hepatotoxicity effect than the standard drug benznidazole (BZN) which has been used during short- and long-term treatment. In the present study, we induced the indeterminate form of Chagas disease in mice with a Y strain of Trypanosoma cruzi and analysed the histopathological data about the effects of NFOH and BZN on different tissues, including the heart, skeletal muscle, liver, kidney, colon, spleen and brain. After infection, BALB/c mice were treated with NFOH (150 mg/kg) and BZN (60 mg/kg) for 60 days and then submitted to immunosuppression using dexamethasone (5 mg/kg) for 14 days. Two trained analysts, as part of a blind evaluation, examined the results using serial sections of 3 mm diameter in two different moments. The results showed reactivation of the disease only in the infected nontreated group (POS). After treatment, amastigote nests were found in the heart, colon, liver and skeletal muscle in the POS group and in the heart and liver of the BZN group. Interestingly, amastigote nests were not found in the NFOH and NEG groups. The histopathological analysis showed fewer tissue lesions and parasite infiltrates in the NFOH group when compared with the BZN and POS groups. We have not observed any increase in the levels of hepatocellular injury biomarkers (AST/ALT) in the NFOH group. These in vivo studies show the potential for NFOH as an effective and safe compound useful as an anti-T. cruzi agent.

Synthesis and anti-platelet activity of novel arylsulfonate--acylhydrazone derivatives, designed as antithrombotic candidates.

In this work, we describe a new class of promising anti-platelet drug candidates with significant antithrombotic activity in vivo. This new series of compounds was structurally planned by modification of known thrombin inhibitors based on the use of acylhydrazone subunit, as a nonpeptide scaffold, and variations at P1 moiety. Three different families of arylsulfonate-acylhydrazone derivatives were designed. The bioassays indicated the first class of derivatives represented by 4f (LASSBio-693) and 4j (LASSBio-743), which were active in inhibiting the platelet aggregation induced by thrombin. The second class represented by compounds 4e (LASSBio-774) and 4h (LASSBio-480) that selectively inhibit the platelet aggregation involving TXA(2) formation. Finally, the third class of derivatives was identified acting as a novel symbiotic agent able to inhibit the platelet aggregation induced by collagen or AA and by thrombin, represented by compounds 4b (LASSBio-694) and 4g (LASSBio-770).