6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis.

A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to survive in vivo and cause disease in animal models. An anthranilate-like compound, 6-FABA, was previously shown to synergize with the host immune response to Mtb infection in vivo. Herein, we present a class of anthranilate-like compounds endowed with good antimycobacterial activity and low cytotoxicity. We show how replacing the carboxylic moiety with a hydrazide led to a significant improvement in both activity and cytotoxicity relative to the parent compound 6-FABA. Several new benzohydrazides (compounds 20-31, 33, 34, 36, 38 and 39) showed good activities against Mtb (0.625 ≤ MIC≤6.25 µM) and demonstrated no detectable cytotoxicity against Vero cell assay (CC50 ≥ 1360 µM). The target preliminary studies confirmed the hypothesis that this new class of compounds inhibits Trp biosynthesis. Taken together, these findings indicate that fluorophenylbenzohydrazides represent good candidates to be assessed for drug discovery.

Finite-Frequency Dissipation in Two-Dimensional Superconductors with Disorder at the Nanoscale.

Two-dimensional superconductors with disorder at the nanoscale can host a variety of intriguing phenomena. The superconducting transition is marked by a broad percolative transition with a long tail of the resistivity as function of the temperature. The fragile filamentary superconducting clusters, forming at low temperature, can be strengthened further by proximity effect with the surrounding metallic background, leading to an enhancement of the superfluid stiffness well below the percolative transition. Finite-frequency dissipation effects, e.g., related to the appearance of thermally excited vortices, can also significantly contribute to the resulting physics. Here, we propose a random impedance model to investigate the role of dissipation effects in the formation and strengthening of fragile superconducting clusters, discussing the solution within the effective medium theory.

Effects of the Filtration on the Biotic Fraction of Extra Virgin Olive Oil.

Filtration is a widely used process in the production of extra virgin olive oil. We studied the influence of filtration performed with cotton filters and cellulose filter press on the biotic components of the oily mass containing probiotic traits in two freshly produced monocultivar extra virgin olive oils. The concentration of bacteria was reduced from 100% to 28%, while that of fungi was reduced from 100% to 44% after filtration, according to the filtration system and the initial contamination of the original monocultivar extra virgin olive oil. Compared with the control, the yeast content in the oil samples filtered with cotton filters was reduced from 37% to 11% depending on the cultivar. In the oil filtered with cellulose filter press, the yeast content reduced from 42% to 16%. The viable yeast that passed through the oily mass during the filtration process with cellulose filter press, unlike all the other samples, were unable to survive in the oil after a month of storage. The possible health benefits of compounds from both the biotic and abiotic fraction of the oil, compared to the control, were significantly low when filtered with the cellulose filter press.

Site-Directed Antibody Immobilization by Resorc[4]arene-Based Immunosensors.

One of the main problems in the development of immunosensors is to overcome the complexity of binding antibodies to the sensor surface. Most immobilizing methods lead to a random orientation of antibodies with a lower binding site density and immunoaffinity. In order to control the orientation of antibody immobilization, several resorc[4]arene derivatives were designed and synthesized. After the spectroscopic characterization of resorc[4]arene self-assembled monolayers (SAMs) onto gold films, the surface coverage and the orientation of insulin antibody (Ab-Ins) were assessed by a surface plasmon resonance (SPR) technique and compared with a random immobilization method. Experimental results combined with theoretical studies confirmed the dipole-dipole interaction as an important factor in antibody orientation and demonstrated the importance of the upper rim functionalization of resorcarenes. Accordingly, resorcarene 5 showed a major binding force towards Ab-Ins thanks to the H-bond interactions with the amine protein groups. Based on these findings, the resorcarene-based immunosensor is a powerful system with improved sensitivity providing new insight into sensor development.

Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis.

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.

In vivo potent BM635 analogue with improved drug-like properties.

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 µM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.