Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes

Background: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi. Objective: Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "in-house" library of both AGH and TSC derivatives and their structurally-related compounds. Method: A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD® software. Result: The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing IC50 values ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms. Conclusion: The promising antileishmanial activity of three AGH’s and three TSC’s was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are under progress, which will help to choose the best hits for in vivo experiments.

Impact of pH and cell medium on the interaction of doxorubicin with lipoic acid cyclodextrin conjugate as the drug carrier

Lipoic acid derivative of cyclodextrin, βCDLip, was used as the drug carrier for doxorubicin (DOX) and the stability constants of the DOX–βCDLip were determined in the environment of the cell medium. The experiments were performed in neutral (pH 7.6) and acidified (pH 6.3) cell media containing more than forty interferences including: amino acids, vitamins, lipids and proteins. We proved that the pH of the medium has a noticeable impact on the affinity of the drug towards the carrier. At neutral pH, the formation constants of the complex are higher than at pH 6.3, what is characteristic for the cancer cells microenvironment. Furthermore, the values obtained in both cell media are twice smaller than the values obtained previously for the same complex but in the absence of common cell media components indicating that there is a competition between DOX and some hydrophobic medium components for the complex formation with βCDLip. On the other hand at pH 7.6, the amount of free DOX is highly limited due to the fact that most of DOX is still in the complexed form, while at pH 6.3 the cell media ingredients become strong interferences in the formation of the complex between DOX and the drug carrier. The observed behaviour is due to partial protonation of DOX and to competition between the drug and the lipoic side arm of cyclodextrin for the cyclodextrin cavity. The stability constants of the DOX–βCDLip complex in acidic pH are similar to the values for DOX with native β-cyclodextrin, demonstrating that the strengthening effect of DOX–CD complex resulting from the presence of cyclodextrin’s aromatic substituent (Lip) occurs only in the case of neutral pH. The high value of the stability constant of the DOX–βCDLip complex in cell medium at pH 7.6 indicates high selectivity of βCDLip ligand which would be of importance both for the effective drug delivery and for its application in DOX sensing devices.

Synthesis and Bioactivity of Thiazolethioacetamides as Potential Metallo-β-Lactamase Inhibitors

Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC50 values of 0.17 to 0.70 μM. For two of them, the IC50 values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against E.coli-ImiS by 2–4 fold. An analysis of the structure–activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors.

Antioxidant and Anti-Inflammatory Activities of the Crude Extracts of Raw and Fermented Tomato Pomace and Their Correlations with Aglycate-Polyphenols

Two tomato pomace (TP) were studied as feedstocks to obtain extracts that are rich in polyphenols. TPs prompt degradation impairs biomass safety, thus naturally present microflora were tested to perform conservation, and own lactic bacteria became predominant after 60 days of treatment. The extracts of TPs and TPs fermented (TPF) were chemically characterized and tested for antioxidant and anti-inflammatory activities. Flavonoids and phenolic acids were classed as aglycone-polyphenols (A-PP), the most bioactive polyphenol fraction. Fermentation led to a reduction of the A-PP amount, but no significant change in composition. Antioxidant power increased, despite the A-PP reduction, for the presence of fermentation metabolites having aromatic-substituent. TP and TPF both have anti-inflammatory properties that were strictly dependent upon the A-PP content. Fermentation preserved the anti-inflammatory activity and the Partial Least Square (PLS) identified as the most active molecules naringenin chalcone, kaempferol, gallic acid, and cinnamic acid, together with the definition of the active dose.

Effect of the aromatic substituent on the para-position of pyridine-bis(oxazoline) sensitizers on the emission efficiency of their EuIII and TbIII complexes

PyboxPh and Pybox2Th bind to Eu and Tb and sensitize the red and green emission of these two lanthanide ions with good efficiencies.

Synthesis and evaluation of 5-imino-4-thioxoimidazolidin-2-one derivatives as antibacterial and antifungal agents

Objective: It was of interesting to synthesize some new 5-imino-4-thioxoimidazolidin-2-one derivatives with different halogenated and alkylated aromatic substituent at N-(1) and N-(3) and evaluation of their expected antibacterial and antifungal activities. Methods: New 5-imino-4-thioxoimidazolidin-2-one derivatives were synthesized through the reaction of different halogenated and alkylated N-arylcyanothioformamides with halogenated and alkylated aryl isocyanates. Results: 5-Imino-4-thioxoimidazolidin-2-ones were obtained in high yields with excellent purity. The activities of imidazolidines as antibacterial and antifungal agents were studied. Some of imidazolidine derivatives displayed significant antibacterial and antifungal activities. Conclusion: 5-Imino-4-thioxoimidazolidin-2-ones were obtained in 77-90% yields with excellent purity. The antibacterial and antifungal activities suggest that some of the imidazole derivatives possess significant antimicrobial activity against B. subtilis, K. pneumonia and C. albicans and moderate activity against S. aureus.