Scientific project of the GF: «Alkyl- and arylsulfochlorination of beta- aminopropioamidoximes using classical and “green” chemistry methods; biological screening of products» (2022‒2024) (IRN AP14870011)

Kayukova L.A.

Project Leader, Chief Scientific Researcher at the A.B. Bekturov Institute of Chemical Sciences, Doctor of Chemical Sciences, Professor

Vologzhanina A.V.

Senior Research Fellow at the RSA "Federal State Budgetary Institution of Science Institute of Oil and Energy Chemicals of the Russian Academy of Sciences named after A.N. Nesmeyanov."

Uzakova A.B.

Researcher at the A.B. Bekturov Institute of Chemical Sciences, Ph.D.

BAITURSYNOVA GULNUR

Researcher at the A.B. Bekturov Institute of Chemical Sciences, Ph.D.

SARTOEVA A.

Engineer at the A.B. Bekturov Institute of Chemical Sciences, bachelor

Duisenali A.M.

Junior Researcher at the A.B. Bekturov Institute of Chemical Sciences, Ph.D.

Yerlanuly A.

Engineer at the A.B. Bekturov Institute of Chemical Sciences, Master's student.

Svetlana Nachinkina

Chief Economist at the A.B. Bekturov Institute of Chemical Sciences.

Kairat Seitbekov

Head of Procurement Department at the A.B. Bekturov Institute of Chemical Sciences

Shulgau Z.

Head of the Toxicology and Pharmacology Laboratory at the National Biotechnology Center, Candidate of Medical Sciences.

Sergazy Sh.

Senior Research Scientist at the Toxicology and Pharmacology Laboratory of the National Biotechnology Center, PhD.

Scientific supervisor of the project: Doctor of Chemical Sciences, Professor Kayukova Lyudmila Alexandrovna

Project start and completion date: July 2022 – December 2024

Objects of research:  β-Aminopropioamidoximes,  2-aminospiropyrazolylammonium alkyl(aryl)sulfonates, O-sulfoalkyl(aryl)amidoximes, reaction activation (ultrasound, microwave, elevated temperature), IR spectroscopy, NMR (¹H and ¹³C) spectroscopy, X-ray diffraction analysis, antiradical activity, antidiabetic activity, antimicrobial activity, cytoprotective activity.

The purpose of the research project: To use the methods of synthesis of classical and “green” chemistry in the alkyl(aryl)sulfochlorination of β- aminopropioamidoximes and to evaluate the competitive formation of O-sulfo derivatives, spiropyrazolinium alkyl(aryl)sulfonates, as well as other possible products.

Project relevance: The project addresses to current issues of the reactivity of multifunctional compounds, using highly effective modern synthetic methods based on new reagents, modern laboratory and spectral equipment and biological tests for a wide range of pharmacological activity to identify the valuable properties of the new sulfoderivatives of β-aminopropioamidoximes for healthcare needs. The project aims to fill the lack of practical results and clarify the discrepant data on the sulfochlorination of amidoximes, which limits the synthetic use of this reaction. The project also addresses to issues of obtaining of the new information about the supposed valuable biological properties of new products.

Results: It is known that sulfochlorination of N-alkyl(aryl)-amidoximes, containing an aromatic substituent at the amidoxime carbon atom, in accordance with the Tiemann rearrangement leads to ureas and N-substituted cyanamides. In addition, the formation of O-arylsulfonylamide oximes is possible.

We carried out alkylsulfochlorination of β-aminopropioamidoximes [β-amino group: thiomorpholin-1-yl, 4-phenylpiperazin-1-yl and benzimidazol-1-yl]. Alkyl substituents in the series of alkylsulfonyl chlorides were: methyl, n-propyl, iso- propyl, n-butyl. Alkylsulfochlorination was carried out in chloroform at room temperature (r.t.). To bind HCl released in the reaction, tributylamine (Bu₃N) was used as a base [conditions (i)].

According to ¹H and ¹³C NMR data and X-ray diffraction data, the reaction of β-aminopropioamidoximes with a number of alkylsulfonyl chlorides in the presence of a base resulted in the isolation of the starting amidoximes, 2-amino-8-phenyl-1,5,8-triazaspiro[4.5]dec-1-ene-5-ium chloride and β-(benzimidazol-1-yl)propioamidoxime hydrochloride. Obviously, Bu3N, due to competitive relationships with the nucleophilic centers of the substrates, forms alkylsulfonyltributyl ammonium chlorides and, in this case, the products of alkylsulfochlorination of β-aminopropioamidoximes cannot be obtained.

The reaction of β-(thiomorpholin-1-yl)-, β-(4-phenylpiperazin-1-yl)- and β- (benzimidazol-1-yl)propioamidoxime with alkylsulfochlorides was carried out in a mixture of water:acetone (4:1) (conditions ii) without the base.

As a result, O-alkylsulfonyl-β-(benzimidazol-1-yl)propioamidoxime hydrochlorides were formed in quantitative yields for β-(benzimidazol-1- yl)propioamidoxime. In the reactions of β-aminopropioamidoximes having six- membered heterocycles [β-(thiomorpholin-1-yl)-, β-(4-phenylpiperazin-1-yl)-] in the β-position with alkylsulfonyl chlorides, 2-aminospiropyrazolylammonium alkylsulfonates hydrochlorides were isolated as the main products.

Biological screening of the synthesized products for a number of in vitro activities revealed high antimicrobial activity of O-alkylsulfonyl-β-(benzimidazol-1- yl)propioamidoximes on gram-positive cocci Staphylococcus aureus ATCC 6538, aerobic gram-positive spore-forming bacilli Bacillus subtilis ATCC 6633, gram- negative bacilli Escherichia coli ATCC 25 922 , aerobic Pseudomonas aeruginosa ATCC.

Alkylsulfoderivatives of β-aminopropioamidoximes have not shown antioxidant activity. There is an example of high α-glucosidase activity, exceeding the activity of the standard acarbose by 30% among the representatives of β-(benzimidazol-1- yl)propioamidoxime O-alkylsulfonates hydrochlorides. Biological screening continues.

Thus, the presence of Bu₃N as a base during the alkylsulfochlorination of β- aminopropioamidoximes does not lead to the interaction of the reagents with the substrates. Alkylsulfochlorination performing without a base in water, according to IR and NMR (¹H and ¹³C) spectroscopy data, made it possible to obtain alkylsulfochlorination  products:  O-alkylsulfonyl-β-(benzimidazol-1- yl)propioamidoxime  hydrochlorides,  2-aminospiropyrazolylammonium alkylsulfonates hydrochlorides.

The presence of an internal basic center, a nitrogen atom in the β-position of β- aminopropioamidoximes, allows alkylsulfochlorination to be carried out without adding an external base. Among the alkylsulfoderivatives of β- aminopropioamidoximes, samples with antimicrobial and α-glucosidase antidiabetic activity were identified that exceeded the activity values of the reference drugs gentamicin and acarbose.

Publications:

Articles:

1. Kayukova , Vologzhanina A., Dorovatovskii P., Yergaliyeva E., Uzakova A., Duisenali A. N-N(+) Bond-forming intramolecular cyclization of O-tosyloxyβ-aminopropioamidoximes and ion exchange reaction for the synthesis of 2-aminospiropyrazolilammonium chlorides and hexafluorophosphates. // International Journal of Molecular Sciences ‒ 2023. ‒ Vol. 24. - 11315. DOI: https://doi.org/10.3390/ ijms241411315

2. Kayukova L., Vologzhanina A. New 2-Aminospiropyrazolylammonium Cation for the Possible Use in the Topical Areas of Ionic Liquids (Review). ‒ Molecules. ‒ 2024. ‒ Vol. 28. ‒ Manuscript ID: molecules-2957431. ‒ Submitted for
3. Каюкова Л.А., Вологжанина А.В., Ерланулы А., Дуйсенали А.М. Наличие основания при алкилсульфохлорировании β-аминопропиоамидоксимов в хлороформе и воде.// Химический журнал Казахстана. ‒ 2024. ‒ № 2. ‒ Подано в печать.

Abstracts:

1. Каюкова Л.А., Вологжанина А.В., Ергалиева Э.М., Узакова А.Б., Жанбырбай С.Б. Синтез хлоридов и гексафторфосфатов 2-амино-1,5-диазаспиро[4.5]дец-1-ен-5- аммониумов. ‒ Труды международной научно-практической конференции «Актуальные направления развития науки и образования в области естествознания». НАО «Казахский национальный женский педагогический университет», г. Алматы, Казахстан. 25 ноября 2022 г. ‒ С. 66‒69.
2. Kayukova L., Yergaliyeva E., Uzakova A., Akhelova A., Dyusembaeva G., Pichkhadze G., Bіsmilda V., Shulgau Z., Gulyaev A., Sergazy Sh. Reactivity and biological activity of β- aminopropioamidoximes drug-like // 19^th Panhellenic Symposium on Medicinal Chemistry https://helmedchem2023.gr/abstracts-book/ (Oral presentation).
3. Yergaliyeva E., Kayukova L., Vologzhanina A., Gubenko M. DFT studies of the β- aminopropioamidoximes arylsulfochlorination // 19^th Panhellenic Symposium on Medicinal Chemistry https://helmedchem2023.gr/abstracts-book / (Flash posters).
4. Каюкова Л.А., Вологжанина А.В., Байтурсынова Г.П., Ергалиева Э.М., Шульгау З.Т. Линейные и перегруппированные продукты нитробензолсульфохлорирования β- аминопропиоамидоксимов, обладающие противодиабетической активностью. Материалы Казахско-Узбекского Симпозиума «Современные проблемы науки о полимерах», АО «Институт химических наук им. А.Б. Бектурова».‒ 2023. ‒ С. 70‒72.

5. Kayukova L.A., Yerlanuly A., Duisenali A.M., Vologzhanina A.V., Belyankova Y.O. Formation of 2-aminospiropyrazolinium and linear compounds at β-aminopropioamidoximes // Proceedings of the 21th International School-Conference «Magnetic Resonance and its Applications – SPINUS-2024» devouted to the 300 Years of SPbU. Saint- Petersburg State University, Russia. 1‒5 April 2024. ‒ P. 340‒342.

Patent documents:

1. Патент на полезную модель № 8787 от 19.01.2024. Применение гидрохлорида О- пара-толуоил-(β-морфолин-1-ил)пропиоамидоксима в качестве субстанции с бактерицидной активностью против туберкулеза бычьего вида M. bovis. / Каюкова Л.А., Узакова А.Б., Ерланұлы А., Тургенбаев К.А., Борсынбаева А.М., Есеналиева А.Б. Государственный реестр полезных моделей Республики Казахстан. www.kazpatent.kz