Seventeen Schiff bases bearing 2-aminothiophene derivatives were designed and synthesized using molecular simplification. The resulting compounds (4a-4q) were evaluated for their in vitro antifungal activity against dermatophytes. Prediction of their druglikeness and pharmacokinetic properties, establishment of their structure-activity relationships (SAR), and cytotoxic evaluation of the most active compounds were performed. Using an eco-friendly procedure, microwave assisted synthesis resulted in compounds in good yields (35-85%). Compounds 4a-4q presented good druglikeness and pharmacokinetic profiles and no cytotoxicity for any cell line tested up to 100 µM. The compounds presenting the best antifungal profiles were 4e, 4f, 4g, 4k, 4l, 4m, 4o and 4p with more than one minimum inhibitory concentration (MIC) value occurring between 16-64 µg mL-1, thus, in some cases better than the reference drug (fluconazole). SAR testing indicated that the presence of halogens and nitro substituents increases antifungal activity. Taken together, the results demonstrate that 2-aminothiophene derivatives are promising lead compounds for the development of antifungal drugs.

Abstract Carbapenem-resistant P. aeruginosa (CRPA) has become a serious public health problem and the biofilm formation aggravates this problem. The study aimed to evaluate the occurrence of β-lactamases and quorum sensing (QS) genes in CRPA isolates, analyze production of biofilm, evaluate the response against meropenem (MPM) and∕or polymyxin B (POL B) and its association with azythromicin (AZT) using quantum dots (QDs) and proteomic analysis. Six CRPA isolates were analyzed. β-lactamases and QS genes were search using specific PCRs and were tested for biofilm production by quantitative technique. A CRPA isolate, containing blaKPC gene and biofilm-producing, was selected to assess its response to therapy using QDs and the MALDI-TOF. The β-lactamase detected was blaKPC in 66.7% of the isolates. All isolates were biofilm producers and carriers of the QS genes. QDs-MPM conjugates triggered the formation of biofilm and the association with AZT inhibited this effect. Proteomics analysis showed that treatments with MPM or POL B suppressed the expression of the transglycosylase protein, while combined therapy with AZT induced expression of the RpoN protein. Thus, this study shows that the use of fluorescence combined with the proteomics analysis was promising to understand how a CRPA strain reacts to antimicrobial treatment.

This study aimed to prepare a complex of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 6CN10, a poorly water soluble 2-aminothiophene derivative with antifungal properties, by freeze-drying technique. The complex was characterized by thermal analysis, infrared/Raman spectroscopy, X-ray diffraction and scanning electron microscopy. In addition, we used the data of the phase solubility study, 1H, and 2D NMR spectroscopy and molecular modeling in order to investigate the interactions between 6CN10 and HP-β-CD. The apparent solubility of 6CN10 with HP-β-CD increased more than 29 fold. The phase solubility assay in water at 25 ºC showed an AP-type curve, with an apparent stability constant K1:1 and K1:2 of 96 and 0.1989 M-1, respectively. The results of IR, NMR and docking indicate that 6CN10 is able to form complexes with HP-β-CD (1:1 and 1:2 stoichiometric ratios), generating the formation of inclusion and preferably, non-inclusion complexes. The antifungal activity against Cryptococcus neoformans demonstrated the superior performance of the complex (46.66 µg mL-1) when compared with the free drug (166.66-333.33 µg mL-1). The present study provides useful information for the potential application of complexation with low soluble compounds and about the type of complex formation between 6CN10 and HP-β-CD.