Study of methods for the preparation of methyl esters of thiosulfonic acids and their biological activity
Students Name: Bobalo Ihor Yuriiovych
Qualification Level: master (ESP)
Speciality: Biotechnology and bioengineering
Institute: Institute of Chemistry and Chemical Technologies
Mode of Study: full
Academic Year: 2022-2023 н.р.
Language of Defence: ukrainian
Abstract: Bobalo I.Yu., Lubenets V.I. (head). S-methyl 4-acetylamidobenzenethiosulfoate production technology project. Master thesis. - Lviv Polytechnic National University, Lviv, 2023. Currently, the priority for industry and medicine is the creation of promising products with a wide spectrum of biological activity. Considering the high synthetic and pharmacological potential of thiosulfonic acid derivatives and their ability to act as nucleophiles and electrophiles in chemical reactions, they are interesting for study. This master’s thesis presents the latest technology for the synthesis of biologically active compounds with a functional thioester group (R1SO2SR2), which are the basis of well-known medicinal preparations. Derivatives of thiosulfonic acids (thiosulfinates, thiosulfonates) have antibacterial and anti-inflammatory properties and are widely used in the chemical, pharmaceutical, and textile industries. Also, the described compounds are of interest as chemical reagents due to their ability to homolytically break the S-S bond by thermolysis or photolysis, and the formation of sulfonyl and sulfenyl radicals. However, despite the great need for thiosulfonates as reagents for chemical synthesis, as well as as antimicrobial substances, only the simplest thiosulfonates are commercially available. The process of synthesis of thiosulfonates is a complex and multi-stage process. In order to solve this problem, the researchers proposed to synthesize thiosulfonates with high yields by using the principles of "green chemistry" and minimizing the number of steps. The synthesis of new thiosulfonates was carried out using such methods of "green chemistry" as: ultrasound, mechanochemistry, microwave irradiation, etc. The master’s thesis presents the results of studies of the biological activity of S-methyl 4-acetylamidobenzenethiosulfoate and its composition with biosurfactants, the prospects for use and their advantages over existing drugs. The purpose of the research is to develop ways and methods of synthesis of S-methyl 4-acetamidobenzenethiosulfonates, to establish the specifics of conducting reactions to obtain the target products and intermediate compounds of their synthesis, to determine the physicochemical properties and structure of the synthesized thioesters, to establish the spectrum of antimicrobial and antifungal activity, using experimental screening and to develop an alternative "green" methodology for the synthesis of target compounds. To obtain compositions of thiosulfonates and biosurfactants with antimicrobial and fungicidal properties. Calculate the material balance of obtaining 1 kg of S-methyl 4-acetamidobenzenethiosulfonate. Develop a basic technological scheme of the process. Determine the material costs of research and the cost of the product. Research objects: nucleophilic substitution reactions and redox reactions in the synthesis of S-methyl 4-acetylamidobenzenethiosulfoate, biological activity of the studied compounds, determination of the relationship between their structure and activity, ultrasonic chemical activation for the development of a more environmentally friendly synthesis method. Research subject: S-methyl 4-acetamidobenzenethiosulfonates for the search of new biologically active compounds. Research methods: organic synthesis, spectral methods (NMR and IR spectroscopy), elemental analysis, thin-layer chromatography, experimental biological screening. Scientific novelty of the obtained results. Data from literary sources on the synthesis, spectrum of biological action of sulfur-containing compounds with disulfide fragments - thiosulfonates and their fields of application are considered. As a result of the conducted biological screening, the prospects of the conducted research on the search for new chemical substances of the thiosulfonate structure with probable antibacterial and fungicidal properties were proven. A block diagram of the main points of work has been created. A green method of obtaining the target product was developed and the conditions were selected for the quantitative yield of the reaction product without the use of solvents and with the minimization of the amount of organic waste. A composite preparation based on S-methyl 4-acetylamidobenzenethiosulfoate and biosurfactants was obtained. The conditions for creating thiosulfonate-biosurfactant compositions were optimized. It has been shown that biocide-biosurfactant compositions have an antimicrobial effect against phytopathogenic bacteria and fungi and are low-toxic compounds. Material calculations were performed to determine the quantities of starting substances necessary to obtain 1 kg of S-methyl 4-acetamidobenzenethiosulfonate according to an 8-stage scheme, and a basic technological scheme for its production was developed. The economic part for calculating laboratory costs for the synthesis of 1000 g of the substance S-methyl 4-acetamidobenzenethiosulfonate is presented. Key words: thiosulfonates, alkyl esters of thiosulfonic acids, biosurfactants, antimicrobial action, fungicidal activity, biological activity, green chemistry. 1. Danhua Ge, Jia-Wei Chen, Pei Xu, Jinyin Pan, Xue-Qiang Chu. 1,n-Thiosulfonylation using thiosulfonates as dual functional reagents Chinese Chemical Letters 33 (2022) 4732–4739 https://doi.org/10.1016/j.cclet.2022.02.019 2. K. Takehiro, L. Bumhee, Ch.Yangyang, Ph. Anh-Tuan, Maynard J., Moreau D., Poblador-Bahamonde A. I., Sakai N., Matile S. Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors. JACS Au 2022, 2, 839?852. Doi:10.1021/jacsau.1c00573 3. Mampuys, P., McElroy, R., Clark, J., Orru, R., & Maesa, B. (2019) Thiosulfonates Emerging Reactants: Synthesis and Applications. Adv. Synth. Catal., 362, 3 – 64. doi:10.1002/adsc.201900864.Yaremkevych O. «Effect of thiosulfonate-biosurfactant compositions on plants grown in oil polluted soil» / Yaremkevych O., Fihurka O., Banya A., Shvets V., Nakonechna A., Karpenko O., Bilushchak H., Karpenko O., Novikov V., Lubenets V.. // Environmental Engineering and Management Journal. 2020. Vol. 19, No. 11. – P. 2003–2012. 4. Lubenets V. «Synthesis and antimicrobial properties of 4-acylaminobenzenethiosulfoacid S-esters» / Lubenets V, Vasylyuk S, Monka N, et al.. // Saudi Pharm J. 2017;25(2):266-274. doi:10.1016/j.jsps.2016.06.007 5. I. Martirosyan, O. Pakholiuk, G. Golodyuk, V. Lutskova, V. Lubenets. Investigation of antimicrobial properties of textile materials after washing. Fibres and Textiles 29(1), 2022, 28-35. DOI: 10.15240/tul/008/2