Organofluorine derivatives of β-D-ribofuranoside were synthesized. Biological tests revealed low toxicity and high insecticidal activity of the obtained compounds.

A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the 1,4,7-triazacyclononane (TACN) moiety was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(ii) complexes of the designer structures showed significant in vitro hydrolytic and oxidative DNA cleavage activity and good antibacterial activity against both Gram-negative and Gram-positive bacteria. The observed activity of all the Cu(ii)-TACN-ciprofloxacin complexes was strongly inhibited in the presence of Cu(ii)-chelating agents, thereby demonstrating "vulnerability" under physiological conditions. However, selected TACN-ciprofloxacin conjugates in their metal-free form efficiently cleaved plasmid DNA under physiological conditions. The lead compound 1 showed good DNase activity which was retained in the presence of strong metal chelators and exhibited excellent antibacterial activity against both Gram-negative and Gram-positive bacteria. Density functional theory calculations combined with quantum mechanics/molecular mechanics simulations suggest a general base-general acid mechanism for the hydrolytic DNA cleavage mechanism by compound 1.

Biological tests of phosphate derivatives of β-D-ribofuranoside were carried out. Compounds with antagonistic, insecticidal, and phytoregulatory activity were identified. The prospects of using phosphate derivatives of β-D-ribofuranoside as a basis for the creation of new environmentally friendly biological preparations for plant protection against diseases and harmful arthropods and for improvement of crop yields were shown.

New derivatives of aminoglycosides with a side chain 1,2-aminoalcohol at the 5" position of ring III were designed, synthesized, and biologically evaluated. The novel lead structure (compound 6), exhibiting substantially enhanced selectivity toward eukaryotic versus prokaryotic ribosome, high readthrough activity, and considerably lower toxicity than the previous lead compounds, was discovered. Balanced readthrough activity and toxicity of 6 were demonstrated in three different nonsense DNA-constructs underlying the genetic diseases, cystic fibrosis and Usher syndrome, and in two different cell lines, baby hamster kidney and human embryonic kidney cells. Molecular dynamics simulations within the A site of the 80S yeast ribosome demonstrated a remarkable kinetic stability of 6, which potentially determines its high readthrough activity.

Organosulfur derivatives of β-D-ribofuranoside were synthesized. Biological tests revealed a low toxicity and a high insecticidal activity in the obtained compounds.

Organosilicon derivatives of β-D-ribofuranoside have been synthesized. Biological tests showed that the synthesized compounds exhibit high insecticidal activity and low toxicity.

The chemistry of selective modification of kanamycin B at the 3′- and 4′-positions of ring I and the evaluation of the resulting derivatives in cell-free translation inhibition and MIC assays are presented. The first synthesis of 3′-epi-kanamycin B (4) and its 3′-amine analogue, 3′-amino-3′- deoxy-epi-kanamycin B (5) was accomplished from commercial kanamycin B. 4′-O-alkylation retained the antibacterial activity of the parent compound and afforded protection against certain kanamycin-resistant strains. The new derivative, compound 5, showed only a moderate reduction in activity and comparative molecular dynamics simulations within the bacterial rRNA decoding site suggested that such a modification can provide excellent positioning of the desired general acid arm in the targeted catalytic antibiotic.

The literature data on the preparation, physicochemical characteristics, and structure of pentaene macrolide antibiotic lienomycin with various biological activities were systematized. Prospects for obtaining and using polyfunctional (multi-target) drugs were considered. The results of the search for hybrid drugs with improved medical and biological properties were generalized. The published data on chemical modification of antibiotics, which affords low-toxic, highly effective semi-synthetic derivatives with an extended spectrum of biological action, were discussed. The prospects for use of genetic engineering techniques for obtaining antibiotic derivatives were noted. The directions for the search of polyfunctional drugs with the view of improving the ecological situation associated with their development and application in medical practice were considered.

In this work we describe a cyber-physical decision support system integrated into the process of researching and developing novel antifungal antibiotics, particularly polyene macrolide antibiotic derivatives. The methods and technologies used to develop the decision support system include modern methods of web-application development (client-server architecture utilizing microservices, asynchronous queues for processing longer tasks), modern methods for developing predictive models (recurrent neural networks), specialized deterministic algorithms, and thin interfaces. The cyber-physical system enables chemists-researchers to make better decisions when selecting potential antifungal drug candidates by predicting the properties of antifungal antibiotics. The models predict toxicity, reaching an average AUC of 0.86 across relevant assays as well as 0.02 mg/kg mean squared error for oral toxicity (LD50, rats). Antifungal activity is predicted using a deterministic algorithm, which was able to correctly separate a set of antifungal and non-antifungal drugs into their respective categories. The mathematical models were trained, tested, and validated on a set of antifungal antibiotic data. Testing showed the models’ accuracy and viability for predicting antifungal antibiotics’ properties.

A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the cyclen moiety was designed and synthesized to investigate their potential for overcoming the general issue of "metallodrug vulnerability" under physiological conditions. The Cu(II) and Co(III) complexes of the new designer compounds were synthesized, and their potential to operate a dynamic, intramolecular cap with DNase activity was explored. The lead Co(III)-cyclen-ciprofloxacin conjugate showed excellent in vitro hydrolytic DNase activity, which was retained in the presence of strong endogenous chelators and exhibited enhanced antibacterial activity relative to the metal-free ligand (in the absence of any adjuvants), thereby demonstrating a "proof of concept" in vitro and ex vivo, respectively, for the dynamic cap hypothesis. The lead conjugate nicked supercoiled plasmid DNA within the fluoroquinolone-gyrase-DNA ternary complex and thereby disabled the function of gyrase, a new mode of action not previously reported for any fluoroquinolone.

Published data on the preparation, physicochemical properties, chemical structure, and biological activity of heptaene macrolide antibiotic perimycin were systematically described. Various directions of practical application of perimycin in agriculture as an eco-friendly antifungal preparation were summarized.

A method was developed for the synthesis of an organofluorine derivative of β-D-ribofuranoside. Biological tests revealed high insecticidal activity and low toxicity of the compound synthesized.

In this chapter, we describe the algorithms for data processing applied as part of an intellectual analysis subsystem of a software system for predicting and researching the properties of antifungal antibiotics. These include models for predicting toxicity based on assays as well as acute oral toxicity. The mathematical models were trained, tested, and validated on different sets of antifungal antibiotic data. Testing showed the models’ accuracy and viability for predicting antifungal antibiotics’ properties.

A library of ciprofloxacin-nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent in vitro hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gram-negative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone-topoisomerase-DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept" in vitro. These ciprofloxacin-nuclease conjugates can therefore serve as models with which to develop next-generation, in vivo functioning catalytic antimicrobials.

Reactions of the tetraene macrolide antibiotic tetramycin B with p-substituted aromatic aldehydes and sodiumcyanoborohydride in the conditions of reaction of reductive amination resultedin formation of its N-benzyl derivatives.Physicochemical and medical and biological properties of obtained derivatives oftetramycin B were studied. Biological investigations showed that N-benzyl derivatives of tetramycin B were low toxicagents and possessed high antifungal activity. The pharmacological testsrevealed that the acute toxicity (LD50) of obtainedderivatives of tetramycin B was 7–8 times low as that of the startingantibiotic. The automated intellectual information system for optimal choice ofthe conditions for rational design, synthesis and using in medical practice ofnovel derivatives of polyene macrolide antibiotics was developed.

In this work we present a software system that enables antifungal antibiotic drug candidate toxicity and likelihood of drug binding prediction. The system is composed of a number of machine learning models and deterministic algorithms. Its implementation utilizes modern software development practices including a client-server architecture with a thin web-client. Testing showed the models’ accuracy and viability for predicting antifungal antibiotics’ properties.

Published data on the preparation, physicochemical properties, chemical structure, and biological activity of tetraene macrolide antibiotic tetramycin were systematically described. Various directions of practical application of tetramycin in agriculture and food industry as an eco-friendly antifungal preparation were summarized.

This review systematically describes the published data on the preparation, physicochemical properties, chemical structure, and biological activity of tetraene macrolide antibiotic lucensomycin. Various applications of lucensomycin, mainly in agriculture and food industry as an eco-friendly fungicidal preparation, were summarized.

Strains of the Gram-positive, thermophilic bacterium Geobacillus stearothermophilus possess elaborate systems for the utilization of hemicellulolytic polysaccharides, including xylan, arabinan, and galactan. These systems have been studied extensively in strains T-1 and T-6, representing microbial models for the utilization of soil polysaccharides, and many of their components have been characterized both biochemically and structurally. Here, we characterized routes by which G. stearothermophilus utilizes mono- and disaccharides such as galactose, cellobiose, lactose, and galactosyl-glycerol. The G. stearothermophilus genome encodes a phosphoenolpyruvate carbohydrate phosphotransferase system (PTS) for cellobiose. We found that the cellobiose-PTS system is induced by cellobiose and characterized the corresponding GH1 6-phospho-β-glucosidase, Cel1A. The bacterium also possesses two transport systems for galactose, a galactose-PTS system and an ABC galactose transporter. The ABC galactose transport system is regulated by a three-component sensing system. We observed that both systems, the sensor and the transporter, utilize galactose-binding proteins that also bind glucose with the same affinity. We hypothesize that this allows the cell to control the flux of galactose into the cell in the presence of glucose. Unexpectedly, we discovered that G. stearothermophilus T-1 can also utilize lactose and galactosyl-glycerol via the cellobiose-PTS system together with a bifunctional 6-phospho-β-gal/glucosidase, Gan1D. Growth curves of strain T-1 growing in the presence of cellobiose, with either lactose or galactosyl-glycerol, revealed initially logarithmic growth on cellobiose and then linear growth supported by the additional sugars. We conclude that Gan1D allows the cell to utilize residual galactose-containing disaccharides, taking advantage of the promiscuity of the cellobiose-PTS system.