Organic Antifungal Drugs and Targets of Their Action

Abstract

: In recent decades, there has been a significant increase in the number of fungal diseases. This is due to a wide spectrum of action, immunosuppressants and other group drugs. In terms of frequency, rapid spread and globality, fungal infections are approaching acute respiratory infections. Antimycotics are medicinal substances endorsed with fungicidal or fungistatic properties. For the treatment of fungal diseases, several groups of compounds are used that differ in their origin (natural or synthetic), molecular targets and mechanism of action, antifungal effect (fungicidal or fungistatic), indications for use (local or systemic infections), methods of administration (parenteral, oral, outdoor). Several efforts have been made by various medicinal chemists around the world for the development of antifungal drugs with high efficacy with least toxicity and maximum selectivity in the area of antifungal chemotherapy. The pharmacokinetic properties of the new antimycotics are also important: the ability to penetrate biological barriers, be absorbed and distributed in tissues and organs, get accumulated in tissues affected by micromycetes, drug metabolism in the intestinal microflora and human organs, and in the kinetics of excretion from the body. There are several ways to search for new effective antimycotics: - Obtaining new derivatives of the already used classes of antimycotics with improved activity properties. - Screening of new chemical classes of synthetic antimycotic compounds. - Screening of natural compounds. - Identification of new unique molecular targets in the fungal cell. - Development of new compositions and dosage forms with effective delivery vehicles. The methods of informatics, bioinformatics, genomics and proteomics were extensively investigated for the development of new antimycotics. These techniques were employed in finding and identification of new molecular proteins in a fungal cell; in the determination of the selectivity of drug-protein interactions, evaluation of drug-drug interactions and synergism of drugs; determination of the structure-activity relationship (SAR) studies; determination of the molecular design of the most active, selective and safer drugs for the humans, animals and plants. In medical applications, the methods of information analysis and pharmacogenomics allows to take into account the individual phenotype of the patient, the level of expression of the targets of antifungal drugs when choosing antifungal agents and its dosage. This review article incorporates some of the most significant studies covering the basic structures and approaches for the synthesis of antifungal drugs and the directions for their further development.

Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

“…56,59 These experiments typically report on both the binding of nisin to lipid II and pore complex formation in the membrane, and deconvolution into specific molecular interactions is therefore difficult. The pores have been shown to be relatively stable (lifetime of seconds as opposed to milliseconds in the absence of lipid II) by electrophysiology, and once the complex is established in vesicles in model studies, nisin does not 3), mutacin 1140 (4), epidermin (5), epilancin 15X (6), geobacillin I (7), and subtilin (8). The nisin-like lipid II binding domains are indicated in blue, nisin-like pore forming domains are indicated in orange, and the hinge region, present in (8), is indicated in purple.…”

“…Several variants have been identified that are more potent than nisin against a subset of Gram-positive and/or Gram-negative bacteria. 72,77−83 Many other class I lanthipeptides such as microbisporicin (NAI-107, 3), mutacin 1140 (4), epidermin (5), epilancin 15X (6), and geobacillin I (7) produced by Microbispora corallina, Streptococcus mutans, Staphylococcus epidermidis (5 and 6), and Geobacillus thermodinitrificans, respectively, contain variants of the lipid II-binding domain of nisin (i.e., the A and B rings; Figure 4). 52,84−87 These compounds have a wide variety of Cterminal ring patterns and sequences, and while all bind lipid II, several (e.g., microbisporicin and mutacin 1140) do not form pores.…”

“…However, the elucidation of biological targets and mode of action (MOA) of these newly discovered natural products have lagged. Decades-long advances in various methodologies have set the framework for detailed MOA studies and avails many future opportunities for such efforts. − …”

Composition and Biological Activity of Vitis vinifera Winter Cane Extract on Candida Biofilm

“…These can be based on our results where we have proved these effects on two Candida species. Even more beneficial in the goal of effective control would be their combination in combination therapy exploring synergism antimycotics [54,55]. Among the most studied plants with antifungal effects against multidrug-resistant species are representatives of Apiacae, Asteraceae, Fabaceae and Myrtaceae [56].…”

Design, Synthesis, and Evaluation of Antifungal Bioactivity of Novel Pyrazole Carboxamide Thiazole Derivatives as SDH Inhibitors

“…In addition, apple valsa canker with an average incidence of more than 50% in the Shanxi Province of China in recent years has severely affected apple production . As of yet, the application of fungicides on crops is one of the most effective strategies for controlling plant diseases. − …”