The biological activities, molecular docking studies, and anticancer effects of 1-arylsuphonylpyrazole derivatives

Article abstract of DOI:10.1080/07391102.2020.1763838

This work is devoted to definition of the direction of reaction between 1-benzenesulfonylimino pyridinium chloride and α- or β-halo-containing sulfamides, chloroacetic acid, 1-chloro-2,3-dihydroxypropane, etc. The optimal conditions for the synchronous reaction of heterocyclization are determined. Benzenesulfonyliminopyridinium chloride was obtained to form pyrazolopyridines with 1,2-polarophiles, and pyridazine pyridines with 1,3-polarophiles. These novel derivatives were found as effective inhibitors of the α-glycosidase with K_i values in the range of 13.66 ± 2.63–60.63 ± 12.71 nM. The molecules (II-X) against enzyme were compared theoretically with the help of molecular docking to compare biological activities. The results were compared with the numerical values of the parameters obtained from molecular docking calculations and found to be in great agreement with the experimental results. However, ADME analysis of molecules was performed. Also, the compounds exhibited significant anticancer effect depending on the doses administered. Communicated by Ramaswamy H. Sarma.

Full text of DOI:10.1080/07391102.2020.1763838

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Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 (Print) 1538-0254 (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
The Biological Activities, Molecular Docking
Studies, and Anticancer Effects of 1-
Arylsuphonylpyrazole Derivatives
Parham Taslimi, Yavuz Erden, Sabir Mamedov, Lala Zeynalova, Nina
Ladokhina, Recep Tas, Burak Tuzun, Afsun Sujayev, Nastaran Sadeghian,
Saleh H. Alwasel & Ilhami Gulcin
To cite this article: Parham Taslimi, Yavuz Erden, Sabir Mamedov, Lala Zeynalova, Nina
Ladokhina, Recep Tas, Burak Tuzun, Afsun Sujayev, Nastaran Sadeghian, Saleh H. Alwasel &
Ilhami Gulcin (2020): The Biological Activities, Molecular Docking Studies, and Anticancer Effects
of 1-Arylsuphonylpyrazole Derivatives, Journal of Biomolecular Structure and Dynamics, DOI:
10.1080/07391102.2020.1763838
To link to this article: https://doi.org/10.1080/07391102.2020.1763838
Accepted author version posted online: 04
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The Biological Activities, Molecular Docking Studies, and Anticancer Effects of 1-
Arylsuphonylpyrazole Derivatives
Parham Taslimi1*, Yavuz Erden2, Sabir Mamedov3, Lala Zeynalova3, Nina Ladokhina3, Recep
Tas1, Burak Tuzun4*, Afsun Sujayev3, Nastaran Sadeghian5, Saleh H. Alwasel6, Ilhami Gulcin5
1Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartin, Turkey
2Department of Molecular Biology and Genetics, Faculty of Science, Bartin University, 74100
Bartin, Turkey
3Laboratory of Faine Organic Synthesis, Institute of Chemistry of Additives, Azerbaijan National
Academy of Sciences, 1029, Baku, Azerbaijan
4Department of Chemistry, Faculty of Sciences, Cumhuriyet University, 58140, Sivas, Turkey
5Department of Chemistry, Faculty of Sciences, Ataturk University, 25240, Erzurum, Turkey
6Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
*Address for Correspondences: Dr. Burak Tüzün, Faculty of Science, Department of Chemistry,
Sivas Cumhuriyet University, 58140-Sivas, Turkey. E-mail: Theburaktuzun@yahoo.com;
*Parham Taslimi Ph.D., Department of Biotechnology, Faculty of Science, Bartin University,
74100 Bartin, Turkey. Email: parham_taslimi_un@yahoo.com; ptaslimi@bartin.edu.tr
ABSTRACT
This work is devoted to definition of the direction of reaction between 1-benzenesulfonylimino
pyridinium chloride and α- or β-halo-containing sulfamides, chloroacetic acid, 1-chloro-2,3-
dihydroxypropane, etc. The optimal conditions for the synchronous reaction of heterocyclization
are determined. Benzenesulfonyliminopyridinium chloride was obtained to form
pyrazolopyridines with 1,2-polarophiles, and pyridazine pyridines with 1,3-polarophiles. These
novel derivatives were found as effective inhibitors of the α-glycosidase with Ki values in the
range of 13.66±2.63-60.63±12.71 nM. The molecules (II-X) against enzyme were compared
theoretically with the help of molecular docking to compare biological activities. The results
were compared with the numerical values of the parameters obtained from molecular docking
calculations and found to be in great agreement with the experimental results. However, ADME
analysis of molecules was performed. Also, the compounds exhibited significant anticancer
effect depending on the doses administered.
Key words: Pyrazolpiridines; pyridazole pyridines; anticancer; enzyme inhibition; molecular
docking

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1. INTRODUCTION
Creation of the new physiological active compounds with desired biological properties, as well
as determination of the link between the chemical structure of synthesized compounds and their
biological activity, and expansion of the range of their actions is among the most important
problems of organic chemistry today. Among condensed heterocycles, pyrazolo- or
pyridazolopyridines, which have a wide spectrum of biological activity, occupy a special place.
Condensed pyridines have a pronounced inhibitory effect of cholinesterase and are widely used
in pharmacy and medicine. Among them, pyridostigmine bromide, quinotilin, and alloxime are
the most known ones. Pyrazolo-pyridines are very strong inhibitors of γ-secretase (Ye et al.,
2013) and dihydropyrazolopyridinyl sulfamides have an autoimmune property (Herrey et al.,
2004). Pyridazonyl sulfamide derivatives exhibit strong antimicrobial activity. As can be seen
from the examples given above, urea and tiourea fragments contain different application areas.
New synthesized compounds and active heterocycle rings show that it is necessary to examine
their various properties. Moreover, there is no systematic study of the effect of cyclic chains and
different functional groups on the chemical properties of the compounds containing the ring in
the literature in relation to various side effects with different side effects (Mohamed, 2007). On
the basis of the synthesized sulphamides obtain functionally substituted pyrazolin-,
pyrazolidone-, -imidazole- and pyrimidine sulfonamides. It is revealed that reaction of
arylsulfochlorides with alkyldiamines with high yield give only bis- sulphamides, and with
carbamyl guanidine only monosulphamide. Synthesized polyamine sulphamides and their
derivatives were tested in different areas. Regularities between structure, composition and
properties are defined (Mamedov, 2007; Farzaliev 2010).
Carbohydrate digestive enzymes are found in the brush border of the intestine and break
down the long-chain polysaccharides into simple absorbable monosaccharide units including
glucose. Indeed, α-glycosidase enzymes play a key role in the lysis of α-glucopyranoside bond in
disaccharides and oligosaccharides to release monosaccharide molecules, which then get
absorbed in the body and thus regulate glucose availability and the degree of postprandial
hyperglycemia. Hence, the inhibition of α-glycosidase is recorded as a prime aim to develop and
discover novel potent and less toxic antidiabetic drugs (Demir et al., 2019; Bilgicli et al., 2019;
Kaya et al., 2019; Çaglayan et al., 2019). Theoretical calculations have become widespread. One
of the main reasons for this is that it is possible to make a clearer comparison of theoretical
calculations in less time. The theoretical method used in this study is molecular docking.
Molecular docking studies compare biological activities of molecules with enzymes (Tüzün
2020; Tüzün and kaya 2018; Mamedova et al., 2019).

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In this study, we performed the design, biological evaluation of some of 1-
arylsuphonylpyrazole- or pyridazin [1,5-a]-pyridine (I-X) which compounds (II-X) were as
effective α-glycosidase inhibitors. Also anticancer studies were performed on these compounds.
Another goal of this work, is compared their inhibitory results with control compounds like
acarbose. Lastly, the biological activity of molecules (II-X) against α-glycosidase enzyme, ID
1R47, was compared. ADME (Absorption, Distribution, Metabolism and Excretion) analysis
(Mermer et al., 2019; Sari et al., 2019; Şener et al., 2019; Altındağ et al., 2019; Singh and Bast
2014; Sağlık et al., 2019; Tao et al., 2013) of the molecules was carried out so that the molecules
can be used as drugs in the future. As a result of this analysis, if the numerical values of the
obtained parameters fall within certain ranges, the molecule is said to be a drug.
2. EXPERIMENTAL
2.1. General chemistry
For synthesis of 1-benzenesulfonamide-2-R-3-Z-1,2-dihydropyrazolo[1,5-a]pyridines (I-III)
0.001 mol of N-benzenesulfonamidepyridinium chloride and 0.001 mol of dipolar (1,2-dichloro-
3-benzenesulfamide, chloroacetic acid, β-bromopropionic acid, 1-chloro-2,3-dihydroxypropane)
were dissolved in 50 ml of ethanol. To the solution was added dropwise a solution of NaOH
(0.002 mol) in ethanol. It was boiled until complete precipitation of NaCl or NaBr (5.5 - 6.0
hour). It was cooled and filtered, then, the filtrate was evaporated to half the volume, cooled and
the precipitated crystals were recrystallized from ethanol.
For synthesis of 6,6-dimethyl-4-oxycyclohexane-2,3-pyrazolo-1-phenylsulfamido [1,5-a]
pyridine (IV) 4.2 g (0.03 mol) of dimedone and 8.12 g (0.03 mol) of pyridinimine were
dissolved in 20 mL of ethanol. With stirring, a 7% alkali solution (1.5 g of NaOH in 40 mL of
ethanol) was added dropwise. Then the mixture was heated for 5-6 hours, half the volume of the
alcohol was distilled off, cooled, 20 mL of water was added and the crystals obtained were
filtered. Then they were recrystallized in ethanol. The method of obtaining is similar to the
method of synthesis of compounds (V-X). However, 0.15 mmol of morpholine is taken, instead
of alkali. The structure of all substances was confirmed by modern physical and chemical
analysis (Tao et al., 2013).
2.2. Enzymes studies
2.2.1. α-Glycosidase enzyme assay
α-Glycosidase inhibitory efficacy of novel 1-arylsuphonylpyrazole- or pyridazin [1,5-a]-pyridine
(II-X) was performed using p-nitrophenyl-D-glycopyranoside (p-NPG) as the substrate,