Nucleus-Independent Chemical Shift (NICS) as a Criterion for the Design of New Antifungal Benzofuranones.

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.

Theoretical Reactivity Study of Indol-4-Ones and Their Correlation with Antifungal Activity.

Chemical reactivity descriptors of indol-4-ones obtained via density functional theory (DFT) and hard-soft acid-base (HSAB) principle were calculated to prove their contribution in antifungal activity [...].

De novo design of non-coordinating indolones as potential inhibitors for lanosterol 14-α-demethylase (CYP51).

The development of antifungal drugs that inhibit lanosterol 14-α-demethylase (CYP51) via non-covalent ligand interactions is a strategy that is gaining importance. A series of novel tetraindol-4-one derivatives with 1- and 2-(2,4-substituted phenyl) side chains were designed and synthesized based on the structure of CYP51 and fluconazole. The antifungal activities of these derivatives against eight human pathogenic filamentous fungi and yeast strains were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds 8a-g displayed activity against Candida tropicalis, Candida guilliermondii and Candida parapsilosis with a minimum inhibitory concentration (MIC) value until 8 µg mL(-1), on the other hand compounds 7a-g showed activity against Aspergillus fumigatus with a MIC value of 31.25 µg mL(-1). A molecular modeling study of the binding interactions between compounds 6, 7d, 8g and the active site of MtCYP51 was conducted based on the computational docking results.

Dibenzo[1,2,5]thiadiazepines are non-competitive GABAA receptor antagonists.

A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA(A) receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I(GABA)), which are mediated by GABA(A) receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA(A) channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA(A) receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy.

Dactylopius opuntiae [Cockerell] Could Be a Source of Antioxidants for the Preservation of Beef Patties.

Dactylopius opuntiae is an insect pest that contains at least carminic acid, which has antioxidant properties. Since there is a relationship between the antioxidant ability and preservative action of compounds applied to meat products, the purpose of this study was to evaluate the antioxidant activity and usefulness of a D. opuntiae extract for beef patty preservation. The insects were bred and processed to obtain a liquid extract. For the extract, its carminic acid content, antioxidant activity against two free radicals, and actions on food quality parameters were determined. The D. opuntiae dry powder contained 2.91% w/w carminic acid, while the liquid extract exhibited an IC50 value of 3437.8 ± 67.8 and 19633.0 ± 674.5 µg/mL against the DPPH and ABTS radicals. Nevertheless, these antioxidant actions were lower than those found in a D. coccus extract. The D. opuntiae extract improved in a short time the redness and yellowness, eliminated the unfavorable effect of their vehicle on the MetMb level, and greatly reduced the TBARS formation. For the first time, an extract of D. opuntiae was applied to beef patties, and its beneficial antioxidant action on meat acceptance parameters was confirmed, which has potential commercial applications.