Pyrazole[3,4-d]pyridazine derivatives: Molecular docking and explore of acetylcholinesterase and carbonic anhydrase enzymes inhibitors as anticholinergics potentials

doi:10.1016/j.bioorg.2019.103213

Bioorganic Chemistry

Volume 92, November 2019, 103213

https://doi.org/10.1016/j.bioorg.2019.103213 Get rights and content

Highlights

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In this study, some Pyrazole[3,4-d]pyridazine derivatives were investigated and performed molecular docking studies.
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The inhibition effects of these compounds were determined against AChE, and CA I and II isoenzymes activities.
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They showed nanomolar inhibition levels on metabolic enzymes.
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These compounds can be important to the treatment of epileptic and AD complications.

Abstract

Recently, the pyridazine nucleus has been widely studied in the field of particular and new medicinal factors as drugs acting on the cardiovascular system. Additionally, a number of thienopyridazines have been claimed to possess interacting biological macromolecules and pharmacological activities such as NAD(P)H oxidase inhibitor, anticancer, and identified as a novel allosteric modulator of the adenosine A1 receptor. The literature survey demonstrates that coumarin, 1,2-pyrazole benzothiazole, and 1,3- thiazole scaffolds are the most versatile class of molecules. In this study, a series of substituted pyrazole[3,4-d]pyridazine derivatives (2a–n) were prepared, and their structures were characterized by Mass analysis, NMR, and FT-IR. These obtained pyrazole[3,4-d]pyridazine compounds were very good inhibitors of the carbonic anhydrase (hCA I and II) isoenzymes and acetylcholinesterase (AChE) with K_i values in the range of 9.03 ± 3.81–55.42 ± 14.77 nM for hCA I, 18.04 ± 4.55–66.24 ± 19.21 nM for hCA II, and 394.77 ± 68.13–952.93 ± 182.72 nM for AChE, respectively. The possible inhibition mechanism of the best-posed pyrazole[3,4-d]pyridazine and pyrazole-3-carboxylic acid derivatives and their interaction with catalytic active pocket residues were determined based on the calculations.

Graphical abstract

Introduction

The pyrazoles are essential parts of many heterocyclic compounds. They have extensive workspace due to biologic activities and medicinal properties [1], [2]. These molecules have potential applications such as antibacterial, antifungal, antibiotics, insecticide, pesticide, biosensors, etc., [3], [4], [5], [6], [7]. Pyrazole molecules are known to exhibit specific properties such as antiviral, antitumor, antidepressant, anti-inflammatory and antioxidant activities [8], [9], [10], [11]. In the medical sector, the pyrazoles are used in the structure of some drugs such as Viagra, Celebrex, and Zerbaxa [12], [13], [14]. Additionally, pyrazole-pyridazine derivatives were used in agricultural products and drug researches due to their diverse biological activities [15]. Furthermore, substituted pyrazoles were used in the polymer structures in terms of optoelectronic properties [16]. The commonly used methods for synthesis of the pyrazole-pyridazine derivatives are reported the cyclocondensation of hydrazine hydrate or monosubstituted hydrazines and 1,3-dicarbonyl compounds [17], [18]. In this study, the synthesis of pyrazole-pyridazine was performed using various hydrazines and substituted pyrazole. The synthesized molecules were characterized by IR, NMR, and Mass analysis.

Carbonic anhydrase (CA) isozymes catalyze the reversible hydration of carbon dioxide (CO₂) to produce bicarbonate anion (HCO₃⁻) and a proton (H⁺) [19], [20]. Hence, these enzyme superfamily members including sixteen isoenzymes are primer controllers of pH outside and within the cell. Diversity in subcellular localization and catalytic activity, carbonic anhydrase isoenzymes show the main range of biological aims with several therapeutic potentials [21], [22]. In particular, inhibitor compounds of hCA I and II isozymes in human cells are utilized as factors for treating glaucoma and edema. Membrane-bound brain-associated hCA IV isoenzyme is involved in pH regulation in neuron cells and glial cells analogously to the tumor-associated CA IX isoform. This plays an important role in progression, acidification of tumors, and metastasis in various cancers. A new approach to therapy of obesity and epilepsy is evaluated by inhibition behavior of special isozymes of CA [23], [24]. Indeed, selective inhibitor compounds of CA isoforms in pathogenic microorganisms is gaining enhancing consideration as a new method of therapy of infectious disease [25].

Acetylcholine (ACh) is the main player as far as Alzheimer's disease (AD) is interesting which is synthesized by choline acetyltransferase (CAT). This area of the brain cell is affected in the pathophysiological phenomenon of the AD [26], [27]. This reasons, finally, a marked difference in ACh and CAT synthesis. CAT amounts are decreased 58–90% in the AD, which raises the severity of dementia [28]. Acetylcholinesterase (AChE) is the enzyme accountable for the degradation of the ACh, which is markedly decreased in the AD. Therefore, these enzymes cholinergic synapses waiting for ACh and choline acetate is a key enzyme responsible for the hydrolysis. AChE enzyme, both three-dimensional structure of the active site amino acid sequence of the enzyme is related to many insects, and nerve transmission in the backbone is highly conserved [29]. Organic compounds with the potential to inhibit AChE enzyme or AChE inhibitors (AChEIs) are also very noteworthy due to their significance in the therapy of multiple neurodegenerative diseases. It is expected that AD, an extensive shape of dementia, will increase its prevalence globally and will be a significant problem for human health in the coming periods [30].

Herein, the facile synthesis to condensation reaction of pyrazole-3-carboxylic acid compounds (1a,b) and pyrazole[3,4-d]pyridazine (2a–n) derivatives have been reported, and their inhibition potential of hCA I, and II isoenzymes were investigated. The most suitable and potent AChE inhibition effects of these molecules are also studied.

Section snippets

Materials and equipment

All chemicals used in this study were purchased from Sigma (Steinheim, Germany) and Merck (Darmstadt, Germany) companies. Bruker DRX-400 MHz FT-NMR spectrometer was employed to obtain the structure of molecules at 1 H (400 MHz) and 13 C (100 MHz) NMR spectra. The infrared spectra were recorded on a Perkin Elmer Precisely Spectrum. Samples were used as pellet form, and the measuring range was from 4.000 to 450 cm⁻¹. An LC/MS spectrometer (Thermo Scientific TSQ-Quantum Access) was used to measure

Chemistry

The pyrazole[3,4-d]pyridazine compounds are the most commonly studied subject in heterocyclic chemistry due to their biologic activities [17]. Therefore, pyrazole[3,4-d]pyridazine compounds were prepared, and spectroscopic methods confirmed their structures. Initially, pyrazole-3-carboxylic acid (1a,b) compounds were prepared by our research group. Pyrazole[3,4-d]pyridazine (2a–n) derivatives were directly obtained by cyclization reaction synthesized 1a and b compounds and various hydrazines as

Conclusion

Finally, a series of pyrazole-3-carboxylic acids (1a and b) and pyrazole[3,4-d]pyridazine (2a–n) derivatives were synthesized. These compounds were analyzed for AChE inhibition properties and hCAs I and II isoforms. Pharmacophores have gained significant importance in many different synthetic drug designs due to their various biological activities and the scaffolds of various bioactive natural compounds. Among the scaffolds of these compounds, thiazole and coumarin have recently attracted

Acknowledgments

The authors would like to thank Dr. Halide Sedef Karaman for providing technical guidance during the docking study of this article and for supporting small drug discovery software.

Declaration of Competing Interest

The authors declared that there is no conflict of interest.

References (54)

A. Çetin et al.
A study on the synthesis and antimicrobial activity of 4-acyl-pyrazoles
J. Saudi Chem. Soc.
(2018)
A.A. Bekhit et al.
Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents
Bioorg. Med. Chem.
(2004)
R. Nagamallu et al.
Synthesis of novel coumarin appended bis(formylpyrazole) derivatives: Studies on their antimicrobial and antioxidant activities
Bioorg. Med. Chem. Lett.
(2016)
P.W. Walker et al.
Comparative effects of pesticides, fenitrothion, and fipronil, applied as ultra-low volume formulations for locust control, on non-target invertebrate assemblages in Mitchell grass plains of south-west Queensland, Australia
Crop Prot.
(2016)
V.C. Diculescu et al.
Applications of a DNA-electrochemical biosensor
TrAC Trends Anal. Chem.
(May 2016)
O.I. El-Sabbagh et al.
Synthesis and antiviral activity of new pyrazole and thiazole derivatives
Eur. J. Med. Chem.
(2009)
B.P. Bandgar et al.
Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, antioxidant and antimicrobial agents
Bioorg. Med. Chem.
(Dec. 2009)
N.K. Terrett et al.
Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
Bioorg. Med. Chem. Lett.
(1996)
S. Ökten et al.
Synthesis, characterization, crystal structures, theoretical calculations and biological evaluations of novel substituted tacrine derivatives as cholinesterase and carbonic anhydrase enzymes inhibitors
J. Mol. Struct.
(2019)
A. Behçet et al.
Synthesis, characterization, and crystal structure of 2-(4-hydroxyphenyl)ethyl and 2-(4-nitrophenyl)ethyl substituted benzimidazole bromide salts: their inhibitory properties against carbonic anhydrase and acetylcholinesterase
J. Mol. Struct.
(2018)

T.D. Penning

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1 H -pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib)

J. Med. Chem.

(1997)

D. Cluck et al.

Ceftolozane–tazobactam: a new-generation cephalosporin

Am. J. Heal. Pharm.

(Dec. 2015)

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Pyrazole[3,4-d]pyridazine derivatives: Molecular docking and explore of acetylcholinesterase and carbonic anhydrase enzymes inhibitors as anticholinergics potentials

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials and equipment

Chemistry

Conclusion

Acknowledgments

Declaration of Competing Interest

J. Saudi Chem. Soc.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Crop Prot.

TrAC Trends Anal. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Mol. Struct.

J. Mol. Struct.

J. Mol. Struct.

Bioorg. Chem.

J. Biol. Chem.

Int. J. Biol. Macromol.

Biochem. Pharmacol.

Bioorg. Chem.

Bioorg. Med. Chem.

Int. J. Biol. Macromol.

Bioorg. Chem.

Bioorg. Chem.

Eur. J. Med. Chem.

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Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1 H -pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib)

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