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PROCEEDINGS OF UNIVERSITIES. APPLIED CHEMISTRY AND BIOTECHNOLOGY 2021 Vol. 11 No. 3 ИЗВЕСТИЯ ВУЗОВ. ПРИКЛАДНАЯ ХИМИЯ И БИОТЕХНОЛОГИЯ 2021 Том 11 N 3
Brief communication / Краткие сообщения DOI: https://doi.org/10.21285/2227-2925-2021 -11 -3-497-501
Prediction of the biological activity of a compound depending on its NH-acidity
© Galina B. Nedvetskaya*, Yuliya A. Aizina*****
*Irkutsk State University, Irkutsk, Russian Federation ** Irkutsk National Research Technical University, Irkutsk, Russian Federation ***A.E. Favorsky Irkutsk Institute of Chemistry SB RAS, Irkutsk, Russian Federation
Abstract: Acetamides are building blocks for the synthesis of compounds containing pharmacophores in their structure, manifesting a diverse range of biological activity. The drugs based on these substances possess antidiabetic effect and inhibit blood coagulation. Some of them act as chemosensitizers (i.e., cancer cell inhibitors). However, the full potential of these compounds remains to be fully accomplished. In a previous study, we synthesised acetamides with the RCONHCH (R') CCl3 general formula (where R = CH3, CH2Cl; R' = C6H5, C6H4CH3, C6H4OCH3, C6H4OH) and studied their acid-base behaviour. The NH-acidity of the studied acetamides is controlled by the polar effects of substituents. In this paper, the potential biological activity of the previously obtained acetamides is calculated, and the dependence of their biological potential on the NH-acidity values is elucidated. Prediction of biological activity was carried out using the PASS software. An analysis of the types of biological activity occurring in all compounds allowed us to determine a linear dependence between the probability of biological potential and the value of dissociation constant.
Keywords: acetamides, NH-acidity, dissociation constants, half neutralisation potential, potentiometric titration, PASS
For citation: Nedvetskaya GB, Aizina YuA. Prediction of the biological activity of a compound depending on its NH-acidity. Izvestiya Vuzov. Prikladnaya Khimiya i Biotekhnologiya = Proceedings of Universities. Applied Chemistry and Biotechnology. 2021;11(3):497-501. (In Russian) https://doi.org/10.21285/2227-2925-2021-11-3-497-501
УДК 542.06+57.088
Установление зависимости потенциала биологической активности от NH-кислотности соединения
Г.Б. Недвецкая*, Ю.А. Айзина*****
* Иркутский государственный университет, г. Иркутск, Российская Федерация ** Иркутский национальный исследовательский технический университет, г. Иркутск, Российская Федерация *** Иркутский институт химии им. А.Е. Фаворского СО РАН, г. Иркутск, Российская Федерация
Резюме: Ацетамиды являются строительным материалом для синтеза соединений, содержащих в своей структуре фармакофорные группы, которые проявляют различную биологическую активность. Созданные на их основе препараты обладают противодиабетическим действием, являются ингибиторами фактора свертывания крови, некоторые действуют как хемо-сенсибилизаторы (т.е. блока-торы раковых клеток). Однако в полной мере возможности этих соединений не раскрыты. Ранее нами были синтезированы ацетамиды с общей формулой RCONHCH(R')CCl3 (где R = CH3, CH2Cl; R' = C6H5, C6H4CH3, C6H4OCH3, C6H4OH) и изучено их кислотно-основное поведение. Показано, что NH-кис-лотность исследованных ацетамидов контролируется полярным эффектом заместителей. Целью настоящей работы являлся расчет потенциальной биологической активности полученных ранее ацетамидов и установление зависимости биологического потенциала от величины NH-кислотности этих соединений. Прогноз биологической активности осуществлен с использованием компьютерной программы PASS. В результате отбора активностей, встречающихся во всех соединениях, установлена линейная зависимость вероятности наличия биологической активности от величины константы диссоциации соединения.
Ключевые слова: ацетамиды, NH-кислотность, константы диссоциации, потенциал полунейтрализации, потенциометрическое титрование, PASS
Nedvetskaya G.B., Aizina YuA. Prediction of the biological activity of a compound depending Недвецкая Г.Б., Айзина Ю.А. Установление зависимости потенциала биологической..
Для цитирования: Недвецкая Г.Б., Айзина Ю.А. Установление зависимости потенциала биологической активности от ЫИ-кислотности соединения. Известия вузов. Прикладная химия и биотехнология. 2021. Т. 11. N 3. С. 497-501. https://doi.org/10.21285/2227-2925-2021-11-3-497-501
INTRODUCTION
Acetamids are one of the most important compound classes from the chemical point of view. They are a building material for creating compounds which contains several pharmacophore groups in their structure. Such compounds, of course, have a biological activity. Acetamids are a part of drugs with diabetic inhibitor1, coagulation factor inhibitor [1] and some of them are blockers for the cancer cells [2, 3]. Acetamids exhibit anticonvulsant [4], antiviral [5], analgesic [6] and insecticides [7] activities.
The possibilities of these compounds are not fully understood. Acetamids with general structure RCONHCH(R')CCl3 (R = CH3, CH2Cl; R' = C6H5, C6H4CH3, C6H4OCH3, C6H4OH) had been studied by us before. The polar effect of substituents controls NH-acidic of the studied compounds [8].
The main idea of this project is to establish the NH acidic potential dependence and biological activity. Our work consists of two stages. We use the PASS online program for the previously obtained acetameds [9] and compare with NH value biological potential [8].
EXPERIMENTAL PART
We used the PASS (Prediction of Activity Spectra for Substances) on-line program criteria biologi-
cal activity assessment. It is a useful tool to make a quick forecasting of diverse biological activity [10, 11]. PASS is a software product designed as a tool for evaluating the general biological potential of an organic drug-like molecule. This program predicts a lot of types of biological activities based on the organic compounds structure [12, 13].
RESULTS AND DISCUSSION
The dissociation constant acetamids pKA (NH-acidity) has been determined the potentiometric method on «Expert-001» [14-18] as well as biological activity factors (Pa) substances. Table contains the results of the biological activity evaluation acetamids.
Table depicts dissociation constant acetamids due to different (R) substituents of substances. However, substituents equidistant from the -CONH-active center and this fact affects the constant compounds I—IV dissociation. The acidity span (pKA) of these compounds varies slightly (from 12 to 14 units). The main contribution to the - NH group proton mobility and the acidity of these compounds made by the presence of chlorine near the active center. Therefore, these compounds acidity increases to 12 units in comparison with the previously described compounds [19]. In compound V, there
Relationship between biological activity (Pa) and NH-acidity (pKA) of acetamides Взаимосвязь биологической активности (Ра) и NH-кислотности (pKa) ацетамидов
The forms of biological activities
Pa
pKA (12.03)
pKA (12.33)
III
pKA (12.68)
IV
pKA (12.86)
V
pKA (14.06)
1. Phobic disorders treatment
2. Chloride peroxidase inhibitor
3. Fusarinine-C ornithinesterase inhibitor
4. Complement factor D inhibitor
5. Enteropepti-dase inhibitor
6. Hematopoietic inhibitor
7. Angiogenesis inhibitor
8. Transglutaminase 2 inhibitor
0.767
0.585
0.580
0.577
0.558
0.541 0.426 0.343
0.660
0.525
0.487
0.483
0.462
0.486 0.393 0.303
0.598
0.398
0.475
0.474
0.459
0.445 0.386 0.291
0.573
0.394
0.473
0.415
0.428
0.395 0.327 0.276
0.772 0.553 0.634 0.600 0.391 0.512
1Машковский М.Д. Лекарственные средства: пособие для врачей. 16-е изд., перераб., испр. и доп. М.: Новая волна. 2012. 1216 с.
II
Nedvetskaya G.B., Aizina YuA. Prediction of the biological activity of a compound depending .. Недвецкая Г.Б., Айзина Ю.А. Установление зависимости потенциала биологической ..
is a donor methyl group near the active center that reduces proton mobility with nitrogen, so the acid strength of this compound is significantly reduced (pKA=14.08).
We chose only those activities which are found in all compounds and analyzed them.
Table presents linear relation biological activity and NH-acidic for the first acetamides. The probability biological activity increases with growing coefficient acidity of the compounds. In case of the (V) last compound the probability of the 1-4 species biological activities dramatically increases. Meanwhile, 7 and 8 species show zero biological activity.
The NH-acidity compound decrease can be explained by the inverse relationship. According to the list of references [12], there are nootropic properties which contain chlorine compound. There have not been any nootropic activities found despite the presence of three or four chlorine atoms in research compounds.
CONCLUSION
Acetamids I-V biological activity theoretical prediction was made. NH value biological potential line dependence on compound dissociation constant value has been set.
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INFORMATION ABOUT THE AUTHORS
Galina B. Nedvetskaya,
Cand. Sci. (Chemistry), Associate Professor, Irkutsk State University,
СВЕДЕНИЯ ОБ АВТОРАХ
Недвецкая Галина Борисовна,
к.х.н., доцент,
Иркутский государственный университет,
Nedvetskaya G.B., Aizina YuA. Prediction of the biological activity of a compound depending .. Недвецкая Г.Б., Айзина Ю.А. Установление зависимости потенциала биологической .
1, Karl Marx St., Irkutsk, 664003,
Russian Federation,
e-mail: galinanedvetskaya@gmail.com
Yuliya A. Aizina,
Cand. Sci. (Chemistry), Associate Professor, National Research Irkutsk State Technical University,
83, Lermontov St., Irkutsk, 664074, Russian Federation, e-mail: aizina@ex.estu.edu; Reseacher,
A.E. Favorsky Irkutsk Institute of Chemistry SB RAS,
1, Favorsky St., Irkutsk, 664033,
Russian Federation,
El e-mail: aizina_yulia@irioch.irk.ru
Contribution of the authors
The authors contributed equally to this article.
Conflict interests The authors declare no conflict of interests regarding the publication of this article.
The final manuscript has been read and approved by all the co-authors.
The article was submitted 13.03.2021. Approved after reviewing 29.05.2021. Accepted for publication 30.08.2021.
664033, г. Иркутск, ул. К. Маркса, 1,
Российская Федерация,
e-mail: galinanedvetskaya@gmail.com
Айзина Юлия Александровна,
к.х.н., доцент,
Иркутский национальный исследовательский
технический университет,
664074, г. Иркутск, ул. Лермонтова, 83,
Российская Федерация,
e-mail: aizina@ex.istu.edu;
научный сотрудник,
Иркутский институт химии им. А.Е. Фаворского СО РАН,
664033, г. Иркутск, ул. Фаворского, 1, Российская Федерация, И e-mail: aizina_yulia@irioch.irk.ru
Заявленный вклад авторов
Все авторы сделали эквивалентный вклад в подготовку публикации.
Конфликт интересов
Авторы заявляют об отсутствии конфликта интересов.
Все авторы прочитали и одобрили окончательный вариант рукописи.
Поступила в редакцию 13.03.2021. Одобрена после рецензирования 29.05.2021. Принята к публикации 30.08.2021.
