Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of Pseudomonas aeruginosa Quorum Sensing Signal as New Anti-Biofilm Agents.

Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a "critical priority" pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 µM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization.

Imidazo[1,2-b]pyridazine as privileged scaffold in medicinal chemistry: An extensive review.

Imidazo[1,2-b]pyridazine scaffold represents an important class of heterocyclic nucleus which provides various bioactives molecules. Among them, the successful kinase inhibitor ponatinib led to a resurgence of interest in exploring new imidazo[1,2-b]pyridazine-containing derivatives for their putative therapeutic applications in medicine. This present review intends to provide a state-of-the-art of this framework in medicinal chemistry from 1966 to nowadays, unveiling different aspects of its structure-activity relationships (SAR). This extensive literature surveil may guide medicinal chemists for the quest of novel imidazo[1,2-b]pyridazine compounds with enhanced pharmacokinetics profile and efficiency.

Plasmablastic lymphoma as a manifestation of the human immunodeficiency virus: Case report.

Plasmablastic lymphoma is a rare subtype of non-Hodgkin's lymphoma, which generally presents an aggressive clinical course and low survival rates. It is strongly associated with HIV infection and the most common site of involvement of the territory of the head and neck is Waldeyer's lymphatic ring, followed by the gastrointestinal tract, lymph nodes and skin. The morphological characteristics of PBL in the oral cavity / jaw in the context of HIV infection show diffuse sheets of large immunoblastic cells with abundant cytoplasm, vesicular chromatin and prominent nucleus, a small located in the center with plasma cells differentiation. The main goal of this article is to review the literature of the plasmablastic lymphoma and report a case. Key words:Plasmablastic lymphoma, PBL, HIV, AIDS, Non Hodgkin Lynphoma.

Differential expression of porcine microRNAs in African swine fever virus infected pigs: a proof-of-concept study.

BACKGROUND: African swine fever (ASF) is a re-expanding devastating viral disease currently threatening the pig industry worldwide. MicroRNAs are a class of 17-25 nucleotide non- coding RNAs that have been shown to have critical functions in a wide variety of biological processes, such as cell differentiation, cell cycle regulation, carcinogenesis, apoptosis, regulation of immunity as well as in viral infections by cleavage or translational repression of mRNAs. Nevertheless, there is no information about miRNA expression in an ASFV infection. METHODS: In this proof-of-concept study, we have analyzed miRNAs expressed in spleen and submandibular lymph node of experimentally infected pigs with a virulent (E75) or its derived attenuated (E75CV1) ASFV strain, as well as, at different times post-infection with the virulent strain, by high throughput sequencing of small RNA libraries. RESULTS: Spleen presented a more differential expression pattern than lymph nodes in an ASFV infection. Of the most abundant miRNAs, 12 were differentially expressed in both tissues at two different times in infected animals with the virulent strain. Of these, miR-451, miR-145-5p, miR-181a and miR-122 presented up-regulation at late times post-infection while miR-92a, miR-23a, miR-92b-3p, miR-126-5p, miR-126-3p, miR-30d, miR-23b and miR-92c showed down-regulation. Of the 8 differentially expressed miRNAs identified at the same time post-infection in infected animals with the virulent strain compared with animals infected with its attenuated strain, miR-126-5p, miR-92c, miR-92a, miR-30e-5p and miR-500a-5p presented up-regulation whereas miR-125b, miR-451 and miR-125a were down-regulated. All these miRNAs have been shown to be associated with cellular genes involved in pathways related to the immune response, virus-host interactions as well as with several viral genes. CONCLUSION: The study of miRNA expression will contribute to a better understanding of African swine fever virus pathogenesis, essential in the development of any disease control strategy.