Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::P_pqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.

Intestinal parasitic infections have been considered a relevant public health problem due to the increased incidence worldwide. In developing countries, diarrhea and gastrointestinal symptoms cause impaired work capacity in adults and delayed rate growth in children. Enteric infections of unknown etiology can often lead to misdiagnosis, increased transmission, and morbidity. The aim of this study was to determine the prevalence of intestinal parasites in a young adult population and their pets. Stool samples from 139 university students and 44 companion animals were subjected to microscopy diagnosis using wet mounts, concentration by zinc sulphate flotation and staining techniques (Kinyoun and trichrome stain). Molecular diagnosis of protozoa was also performed by conventional PCR. The mean age was 24 years, 54% individuals were female, 46% were men, and 66% had at least one pet. The overall prevalence for at least one parasite was 74.8% and the rate of polyparasitism was 37.5%. Eighty-three patients (59.7%) were positive for Blastocystis spp., followed by Cryptosporidium spp. 24.5%, Endolimax nana 13.6%, Entamoeba dispar/E. moshkovskii 7.8% and Giardia intestinalis 1.4%. Molecular diagnosis substantially improved Cryptosporidium spp. and Blastocystis spp. detection and allowed to distinguish E. histolytica from commensals in the Entamoeba complex. Student’s pets were also examined for parasitism. Samples from 27 dogs, 15 cats, one rabbit and one hen were analyzed, and parasites were detected in 30 (68.2%) as follows: Cryptosporidium spp. (24) Giardia spp. (4), hookworm (3), Endolimax nana (2) and Toxoplasma gondii (1). Overall, university students showed high prevalence of parasitism and polyparasitism suggesting exposure to parasite infected animals and contaminated environments. Cryptosporidium spp. was the predominant pathogen in human and domestic animals, and it was only detected by PCR, pointing out the need for sensitive tests in diagnosis and surveillance. Control strategies to prevent the effects of parasitic infections in young population should consider pets as reservoirs and transmission source.

The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC₅₀ ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC₅₀ 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC₅₀ < 1 μM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

A versatile method for the synthesis of new oxindoles was developed by the reaction between substituted isatins and 5-aminopyrazoles. The reaction was carried out at room temperature in ethanol using p-toluenesulfonic acid as the catalyst. The products were obtained with acceptable to excellent yields (44–96%). Structures of the new compounds were unambiguously established by spectroscopic and analytical techniques. The antibacterial activity was determined by microdilution assays. Compounds 3b, 3e, and 3g showed antistaphylococcal activity, particularly compound 3e displayed a potent activity against the vancomycin intermediate Staphylococcus aureus (VISA). Compounds 3i, 3j, and 3o inhibited Neisseria gonorrhoeae growth.