Synthesis, In Vivo Anticonvulsant Activity Evaluation and In Silico Studies of Some Quinazolin-4(3H)-One Derivatives.

Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.

TET2 rs1548483 SNP Associating with Susceptibility to Molecularly Annotated Polycythemia Vera and Primary Myelofibrosis.

BACKGROUND: The complexity of myeloproliferative neoplasms (MPNs) cannot be characterized by acquired somatic mutations alone. Individual genetic background is thought to contribute to the development of MPNs. The aim of our study was to assess the association between the TET2 rs1548483 single nucleotide polymorphism (SNP) and the susceptibility to polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) or chronic myeloid leukemia (CML). METHODS: We evaluated the TET2 rs1548483 SNP through real-time PCR in 1601 MPN patients out of which 431 with PV, 688 with TE, 233 with PMF, 249 with CML and 197 controls. We included only patients with a molecularly proven driver mutation, such as JAK2 V617F, CALR or BCR-ABL1. RESULTS: Significant association between TET2 rs154843 variant allele and JAK2 V617F-positive PV and PMF (OR = 1.70; 95% CI: 1.01-2.91; p-value = 0.046, and OR = 2.04; 95% CI: 1.10-3.77; p-value = 0.024, respectively), and type 2 CALR-positive PMF (OR = 2.98; 95% CI: 1.12-7.93; p-value = 0.035) was noted. CONCLUSIONS: The TET2 rs1548483 SNP is associated with the susceptibility to molecularly annotated PV and PMF.

Design, Synthesis and Biological Evaluation of New Piperazin-4-yl-(acetyl-thiazolidine-2,4-dione) Norfloxacin Analogues as Antimicrobial Agents.

 In an effort to improve the antimicrobial activity of norfloxacin, a series of hybrid norfloxacin-thiazolidinedione molecules were synthesized and screened for their direct antimicrobial activity and their anti-biofilm properties. The new hybrids were intended to have a new binding mode to DNA gyrase, that will allow for a more potent antibacterial effect, and for activity against current quinolone-resistant bacterial strains. Moreover, the thiazolidinedione moiety aimed to include additional anti-pathogenicity by preventing biofilm formation. The resulting compounds showed promising direct activity against Gram-negative strains, and anti-biofilm activity against Gram-positive strains. Docking studies and ADMET were also used in order to explain the biological properties and revealed some potential advantages over the parent molecule norfloxacin.

New N-(oxazolylmethyl)-thiazolidinedione Active against Candida albicans Biofilm: Potential Als Proteins Inhibitors.

C. albicans is the most frequently occurring fungal pathogen, and is becoming an increasing public health problem, especially in the context of increased microbial resistance. This opportunistic pathogen is characterized by a versatility explained mainly by its ability to form complex biofilm structures that lead to enhanced virulence and antibiotic resistance. In this context, a review of the known C. albicans biofilm formation inhibitors were performed and a new N-(oxazolylmethyl)-thiazolidinedione scaffold was constructed. 16 new compounds were synthesized and characterized in order to confirm their proposed structures. A general antimicrobial screening against Gram-positive and Gram-negative bacteria, as well as fungi, was performed and revealed that the compounds do not have direct antimicrobial activity. The anti-biofilm activity evaluation confirmed the compounds act as selective inhibitors of C. albicans biofilm formation. In an effort to substantiate this biologic profile, we used in silico investigations which suggest that the compounds could act by binding, and thus obstructing the functions of, the C. albicans Als surface proteins, especially Als1, Als3, Als5 and Als6. Considering the well documented role of Als1 and Als3 in biofilm formation, our new class of compounds that target these proteins could represent a new approach in C. albicans infection prevention and management.

Lipophilicity evaluation of some thiazolyl-1,3,4-oxadiazole derivatives with antifungal activity.

The chromatographic behavior of a series of thiazolyl-1,3,4-oxadiazoles with antifungal activity was studied by reverse-phase thin-layer chromatography (RP-TLC). The lipophilicity parameters derived from RP-TLC were correlated with the data derived from liquid-chromatography mass-spectrometry. Good linear relationships were observed between the chromatographic lipophilicity parameters and the theoretical lipophilicity descriptors (logP) generated by various computer software and internet modules. Principal component analysis, applied on the experimental chromatographic lipophilicity indices and the theoretically calculated logP, enabled us to obtain a lipophilicity chart for better vizualization of the similarities and differences of the investigated compounds, which were grouped by k-means clustering in two congeneric classes.

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking.

Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-analysis of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochemical characterisation confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compounds have a reduced activity against bacterial cell viability. However, the compounds prevent biofilm formation at very low concentrations, especially in the case of E. faecalis. Molecular docking studies performed estimate that this is most likely due to the inhibition of Sortase A. The new compounds could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.

COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.

The effect of some 4,2 and 5,2 bisthiazole derivatives on nitro-oxidative stress and phagocytosis in acute experimental inflammation.

Nineteen bisthiazoles were tested in order to assess their anti-inflammatory and antioxidant properties. First, we evaluated the in vitro direct antioxidant capacity of the bisthiazoles using the DPPH radical scavenging method. Then, the anti-inflammatory effect was tested in acute rat experimental inflammation by measuring the acute phase bone marrow response, the phagocytic capacity and the serum nitro-oxidative stress status. Although none of the substances showed significant direct antioxidant potential in the DPPH assay, most of them improved serum oxidative status, when administered to rats with inflammation. Four of the bisthiazoles proved to have good anti-inflammatory properties, similar or superior to that of equal doses meloxicam.