1,3-Thiazine, 1,2,3,4-Dithiadiazole, and Thiohydrazide Derivatives Affect Lipid Bilayer Properties and Ion-Permeable Pores Induced by Antifungals

Abstract

Over the past decade, thiazines, thiadiazoles, and thiohydrazides have attracted increasing attention due to their sedative, antimicrobial, antiviral, antifungal, and antitumor activities. The clinical efficacy of such drugs, as well as the possibility of developing resistance to antimicrobials, will depend on addressing a number of fundamental problems, including the role of membrane lipids during their interaction with plasma membranes. The effects of the eight 1,3-thiazine-, 1,2,3,4-dithiadiazole-, and thiohydrazide-related compounds on the physical properties of model lipid membranes and the effects on reconstituted ion channels induced by the polyene macrolide antimycotic nystatin and antifungal cyclic lipopeptides syringomycin E and fengycin were observed. We found that among the tested agents, the fluorine-containing compound N-(3,5-difluorophenyl)-benzenecarbothiohydrazide (C6) was the most effective at increasing the electric barrier for anion permeation into the hydrophobic region of the membrane and reducing the conductance of anion-permeable syringomycin pores. A decrease in the membrane boundary potential with C6 adsorption also facilitated the immersion of positively charged syringomycin molecules into the lipid bilayer and increases the pore-forming ability of the lipopeptide. Using differential scanning microcalorimetry, we showed that C6 led to disordering of membrane lipids, possibly by potentiating positive curvature stress. Therefore, we used C6 as an agonist of antifungals forming the pores that are sensitive to membrane curvature stress and lipid packing, i.e., nystatin and fengycin. The dramatic increase in transmembrane current induced by syringomycin E, nystatin, and fengycin upon C6 treatment suggests its potential in combination therapy for treating invasive fungal infections.

Synthetic aspects of 1,4- and 1,5-benzodiazepines usingo-phenylenediamine: a study of past quinquennial

“…The catalyst promoted the reaction of OPD (1) with dimedone (21b) and aromatic aldehydes (22) to synthesize 1,5-BZDs (23) and give 94% yield in 30 min using EtOH at RT. The protocol also involved the reaction of OPD (1) with Meldrum's acid (24) and isocyanide (25) to prepare BZD derivatives (26) in 91% yield in 50 min using a DCM solvent at RT. The authors optimized some other catalysts such as MgO NPs, triethylamine, Nano-CuO, Nano-CeO 2 , CeO 2 /CuO and CeO 2 / CuO@GQDs, but they did not give satisfactory results with respect to the reaction time and yield (Scheme 9; Method 1) and (Scheme 10; Method 1).…”

“…Esfandiari et al 81 formulated a one-pot synthesis of 1,5-BZDs (23/26) using OPD (1), dimedone (21b), aryl aldehyde (22) or isocyanide (25) and Meldurm's acid (24) with chitosan operationalized by triacid imide as an efficient catalyst. The use of 7 mg catalyst gave high yields (93%) in 40 min.…”

“…Shaabani et al 95 devised a green methodology for the synthesis of 1,5-BZDs (44) using OPD (1), ketones (10) and isocyanides (25) with vitamin C (L-ascorbic acid) as a catalyst in water as a solvent. The authors obtained excellent yields in a 5 h reaction time at RT.…”

“…1,5-BZDs possess tremendous activities such as amnesia, 13 anticonvulsant, 14 hypnotics, 15 analgesic, 16 antimalarial, 17 antifungal, 18 antibacterial, 19,20 anti-viral, 21 anti-HIV, 22 anti-inflammatory, 23 antitumor, 24 and phytotoxic functions. 25 There are several commercially approved drugs based on 1,5-BZDs such as clobazam, lofendazam, arfendazam, triflubazam, CP-1414S, cystathionine, nevirapine, and telenzepine (Fig. 2).…”