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Article

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic

by
Hamad M. Alkahtani
1,
Abdulrahman A. Almehizia
1,
Mohamed A. Al-Omar
1,
Ahmad J. Obaidullah
1,
Amer A. Zen
2,
Ashraf S. Hassan
3,* and
Wael M. Aboulthana
4
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
2
Chemistry & Forensics Department, Clifton Campus, Nottingham Trent University, Nottingham Ng11 8NS, UK
3
Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo 12622, Egypt
4
Biochemistry Department, Biotechnology Research Institute, National Research Centre, Cairo 12622, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(20), 7125; https://doi.org/10.3390/molecules28207125
Submission received: 6 September 2023 / Revised: 27 September 2023 / Accepted: 11 October 2023 / Published: 17 October 2023
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)

Abstract

:
In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base–pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer’s (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

1. Introduction

Diabetes is a universal health concern that affects millions of individuals worldwide. Diabetes mellitus is a group of metabolic disorders distinguished by chronic hyperglycemia because of defective production of insulin and/or its activity. Diabetes is classified into type 1 and type 2 diabetes. Diabetes mellitus can cause significant complications such as brain injury, amputations, and heart problems [1]. Alzheimer’s disease (AD) is a form of dementia. The symptoms of Alzheimer’s disease are memory loss and neuronal death. Some of the factors that cause Alzheimer’s disease are cardiovascular disease, old age, and psychosocial factors [2]. Arthritis is an inflammation of the joints of the body. There are various types of arthritis. Osteoarthritis is the most widespread joint disease. The complications of arthritis are pain and disability. The disease of arthritis evolves over decades and ends with the loss of joint function [3]. Free radicals are reactive chemical species and have the ability to attack DNA, proteins, and lipids. Also, free radicals have a relationship with diverse diseases, including cancer, aging, and Alzheimer’s disease. Therefore, antioxidants are very important chemical substances that react with free radicals to prevent the oxidation of biomolecules and protect the body from diseases [4]. Recently, medical research has explored the relationship between diverse diseases, their complications, and their causes [5,6,7]. The complications of free radicals are aging and Alzheimer’s disease. Furthermore, aging may cause diabetes mellitus, Alzheimer’s disease, cardiovascular disease, and arthritis (Figure 1). Therefore, it is important to study the effectiveness of compounds and their biological activities to find a more effective and multi-target drug.
Schiff bases (azomethine compounds) have a spectrum of applications in diverse fields such as the organic, pharmaceutical, and medicinal areas [8]. Schiff bases have a broad range of pharmacological activities, including in vitro anti-HIV activity in, for example, Schiff base 1 (prepared from 5-nitrovaniline and sulphadiazine) [9]. Schiff base 2 is an example of the inhibition activities against acetylcholinesterase (anti-Alzheimer’s agent) and α-glucosidase (anti-diabetic agent) [10]. The ferrocenyl–Schiff base 3 possesses antibacterial and antitumor activities [11]. Schiff base 4, which is derived from trans-2-hexenal with cytosine, is a template for anti-arthritic activity [12] (Figure 2). Furthermore, there are some drugs based on Schiff bases, such as nifuroxazide (an antibiotic for susceptible gastrointestinal infection treatment), thiacetazone (used for tuberculosis infection treatment), and dantrolene (a direct-acting skeletal muscle relaxant) [13].
Pyrazole scaffold has attracted some attention because of its effectiveness and applicability in various fields, primarily the pharmaceutical field [14]. An example of its biological activities is compound 5, a pyrazole–benzofuran hybrid, that acts as an α-glucosidase inhibitor (anti-diabetic agent) [15]. Pyrazole derivative 6 displays antifungal activity [16]. Coumarin–pyrazole derivative 7 shows good anticholinesterase and antioxidant activities [17]. Ethyl-1H-pyrazole-4-carboxylate derivative 8 shows multiple activities as anticancer and anti-inflammatory [18]. Chalcone-engrafted pyrazole 9 shows anti-Alzheimer (acetylcholinesterase% inhibition) and anti-diabetic (α-glucosidase and α-amylase% inhibitions) activities [19] (Figure 2). Also, celecoxib (a non-steroidal anti-inflammatory drug), pyrazofurin (a nucleoside analog related to ribavirin), and ramifenazone (that possesses multiple activities as an analgesic, antipyretic, anti-inflammatory, and antimicrobial) are drugs that have pyrazole scaffold in their structures and are on the market [20].
During the last decade, Schiff bases bearing pyrazole scaffold have attracted growing interest in the pharmaceutical and medicinal fields because of their varied biological effectiveness [21]. Schiff base-bearing pyrazole derivative 10 was shown to be an effective antibacterial for Salmonella typhimurium and had anticancer properties against the HeLa cancer cell line [22]. Schiff base-bearing nitroimidazole and pyrazole nuclei 11 demonstrated effective antibacterial activity as an inhibitor against the E. coli FabH receptor [23]. Schiff base-bearing pyrazole sulfonamide derivative 12 possesses significant anti-inflammatory activity towards COX-2 enzyme, with IC50 equal to 38.73 nM and with a selectivity index equal to 17.47. An in vivo rat paw edema assay of compound 12 was demonstrated to have anti-inflammatory activity, reducing paw edema by up to 42.96% [24]. Schiff base-bearing pyrazole skeleton 13 is an example of in vivo antiviral activity that exhibited protection, inhibition, and therapeutic effects against tobacco mosaic virus (TMV) [25] (Figure 2).
As a result of the foregoing facts about the pharmaceutical and medicinal applications of Schiff bases, pyrazole scaffold, and Schiff bases bearing pyrazole scaffold as well as the importance of multi-target compounds in medicinal chemistry [26,27,28,29,30,31,32,33,34], also, based on the concept of the multi-target drug, and in continuation of our cooperation program [35], thus the goal of the current manuscript is to:
  • Synthesize the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
  • Evaluation of in vitro antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties.
  • Study the in silico bioinformatics analysis (physicochemical properties, the bioavailability radar, drug-likeness, and medicinal chemistry) of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
  • Study the molecular lipophilicity potential (MLP) and the molecular polar surface area (PSA) of the derivatives 22a, b and 23a, b.
Figure 3 illustrates the rationale and the studies.

2. Results and Discussion

2.1. Chemistry

5-Aminopyrazoles 19a, b [36] as starting materials were produced according to reported procedures and are shown in synthetic Scheme 1.
The target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), were produced by the one-step reaction strategy, where 5-aminopyrazoles 19a, b were reacted with 2, 5-dimethoxybenzaldehyde (20) or 4-chloro-3-nitrobenzaldehyde (21), respectively, in ethanol absolute [37] as represented in synthetic Scheme 2.
The 1H NMR spectra of the target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), were characterized by a single signal around at δ = 8.64–8.76 ppm for the –N=CH- proton. Also, they were characterized by three signals around at δ = 9.13–9.47, 9.79–10.18, and 11.74–13.01 ppm for the three NH protons which are exchangeable by D2O [37] (see Supplementary Material).

2.2. In Vitro Biological Activities

Antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were estimated according to the reported methods in the literature [38,39,40].

2.2.1. Antioxidant Activities

The antioxidant activities of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were evaluated. The results of the total antioxidant capacity (TAC = mg gallic acid/gm), iron-reducing power (IRP = µg/mL), the scavenging activity against DPPH (IC50 = µg/mL), and ABTS radicals (%) are listed in Table 1.
Table 1 results show that:
  • 5-(2, 5-Dimethoxybenzylideneamino)-3-(4-methoxyphenylamino)-1H-pyrazole derivative 22b exhibited the highest antioxidant activities among all the compounds, which had total antioxidant capacity (TAC) = 42.47 ± 0.09 mg gallic acid/gm, iron-reducing power (IRP) = 24.02 ± 0.05 µg/mL, DPPH radical-scavenging activity (IC50 = 13.20 ± 0.03 µg/mL), and ABTS radical-scavenging activity (%) = 35.11 ± 0.08. After compound 22b in the activity, there was compound 23a, 5-(4-chloro-3-nitrobenzylideneamino)-3-(4-methoxyphenylamino)-N-phenyl-1H-pyrazole derivative, which has total antioxidant capacity (TAC) = 36.85 ± 0.08 mg gallic acid/gm, iron-reducing power (IRP) = 20.84 ± 0.05 µg/mL, DPPH radical-scavenging activity (IC50 = 15.21 ± 0.03 µg/mL), and ABTS radical-scavenging activity (%) = 30.46 ± 0.07.
  • The two compounds 22a and 23b have almost the same antioxidant activities (TAC = 34.75 ± 0.08 and 34.56 ± 0.08 mg gallic acid/gm, IRP = 19.65 ± 0.04 and 19.54 ± 0.04 µg/mL, DPPH (IC50) = 16.22 ± 0.04 and 16.13 ± 0.04 µg/mL, and ABTS (%) = 28.73 ± 0.06 and 28.56 ± 0.06, respectively).

2.2.2. Anti-Diabetic and Anti-Alzheimer’s Activities

Anti-diabetic and anti-Alzheimer’s activities of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were evaluated by figuring out the percentage of the α-amylase and acetylcholinesterase (ACE) inhibitions, respectively. The results of the anti-diabetic and anti-Alzheimer’s activities are detailed in Table 2.
  • In the case of α-amylase inhibition (anti-diabetic activity) and using acarbose as the standard reference (% = 69.11 ± 0.15), we observe that compound 22b showed inhibitor activity of α-amylase (%) = 36.06 ± 0.08, and the next in the activity series is compound 23a with α-amylase inhibition (%) equal to 31.28 ± 0.07. The two compounds 22a and 23b showed almost matching α-amylase inhibition activities equivalent to 29.50 ± 0.06 and 29.34 ± 0.06, respectively.
  • In the case of anti-Alzheimer’s activity and using acetylcholinesterase (ACE) inhibition as an indicator for the activity, we observe that compound 22b showed inhibitor activity of acetylcholinesterase (ACE, %) = 20.71 ± 0.05, and the next is 23a with percentage inhibition of acetylcholinesterase equal to 17.97 ± 0.04. The inhibitor activities of the two derivatives 22a and 23b are almost the same and equal to 16.95 ± 0.04 and 16.85 ± 0.04, respectively.

2.2.3. Anti-Arthritic Activity

The anti-arthritic activities of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were evaluated by figuring out the percentage of the protein denaturation inhibition and the proteinase enzyme inhibition using diclofenac sodium as the standard reference. The results of the anti-arthritic activity are listed in Table 2.
-
In the case of the protein denaturation inhibition, the more potent compound is 23a with an inhibitor percentage equal to 22.56 ± 0.05, and then compound 22b which shows activity equal to 19.57 ± 0.04.
-
In the case of the inhibition of proteinase, we also find that compound 23a (inhibition of proteinase% = 20.71 ± 0.05) is the most active among the Schiff bases bearing pyrazole scaffold, then compound 22b (inhibition of proteinase% = 17.97 ± 0.04), then the compound 18a (inhibition of proteinase% = 16.95 ± 0.04), and finally the compound 23b (inhibition of proteinase% = 16.85 ± 0.04), compared to the standard drug, diclofenac sodium (inhibition of proteinase% = 41.88 ± 0.09). Therefore, the order of activities is diclofenac sodium > 23a > 22b > 22a > 23b.
From the above result of in vitro biological activities studies of Schiff bases bearing pyrazole scaffold 22a, b and 23a, b, we can conclude that the compound 22b displayed significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while the compound 23a displayed significant anti-arthritic activity (Figure 4).

2.3. In Silico Bioinformatics Analysis

2.3.1. Physicochemical Properties

Physicochemical properties affect all aspects of drug action because these properties have some biological or chemical effects on the receptors. Also, the physicochemical properties are essential for the successful formulation of the drugs. Specific physicochemical properties shown to be relevant to oral drugs are size, lipophilicity, ionization, hydrogen bonding, polarity, aromaticity, and shape [41]. The physicochemical properties of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were yielded using the ADMETlab 2.0 website https://admetmesh.scbdd.com/ (accessed on 11 August 2023)
The physicochemical properties of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) include:
-
Molecular weight (MW): sum of the atomic weight values of the atoms in a molecule (optimal: 100~600).
-
Volume: van der Waals volume.
-
Density: density = MW/volume.
-
The number of hydrogen bond acceptors (nHA): sum of all O and N (optimal: 0~12).
-
The number of hydrogen bond donors (nHD): sum of all OHs and NHs (optimal: 0~7).
-
The number of rotatable bonds (nRot): (optimal: 0~11).
-
Number of rings (nRing): smallest set of smallest rings (optimal: 0~6).
-
Number of atoms in the biggest ring (MaxRing): number of atoms involved in the biggest ring (optimal: 0~18).
-
Number of heteroatoms (nHet): number of non-carbon atoms (hydrogens included, optimal: 1~15).
-
The formal charge (fChar) (optimal: −4~4).
-
Number of rigid bonds (nRig): number of non-flexible bonds, as opposed to rotatable bonds (optimal: 0~30).
-
Flexibility: flexibility = nRot/nRig.
-
Stereocenters: number of stereocenters (optimal: ≤2).
-
Topological polar surface area (TPSA): sum of tabulated surface contributions of polar fragments (optimal: 0~140).
-
logS: the logarithm of aqueous solubility value (optimal: −4~0.5 log mol/L).
-
logP: the logarithm of the n-octanol/water distribution coefficient (optimal: 0~3 log mol/L).
-
logD7.4: the logarithm of the n-octanol/water distribution coefficients at pH = 7.4 (optimal: 1~3 log mol/L).
The detailed information on the physicochemical properties of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) can be seen in Table 3.
Also, the bioavailability radar of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) for physicochemical properties is shown in Figure 5. The pink area represents the optimal lower limit of physicochemical properties, while the buff area represents the optimal upper limit of physicochemical properties. The blue line represents the physicochemical properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
From Figure 5, we can conclude that the blue line of the physicochemical properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) is in the optimal range between the buff area (the optimal upper limit) and the pink area (the optimal lower limit) except for three properties (logS, logP, and logD7.4) which indicate the solubility property. logS (the logarithm of aqueous solubility value) is less than the optimal lower value. But, logP (the logarithm of the n-octanol/water distribution coefficient) and logD7.4 (the logarithm of the n-octanol/water distribution coefficients at pH = 7.4) are more than the optimal upper limit. Therefore, we can deduce that these compounds, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), may be orally bioavailable.

2.3.2. Drug-Likeness

Drug-likeness of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) was predicted using the ADMETlab 2.0 website https://admetmesh.scbdd.com/ (accessed on 11 August 2023).
Detailed information about the drug-likeness of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) can be seen in Table 4.
Drug-likeness was designated based on the physicochemical properties for discovering oral drug candidates [42]. We used three rules, namely the Lipinski rule, the GSK rule, and Pfizer rule, for illustrating drug-likeness.
-
Lipinski rule: this rule held four parameters and its requirements are MW ≤ 500, logP ≤ 5, nHA ≤ 10, and nHD ≤ 5 [43].
-
GSK rule: this rule depends on molecular weight (MW) and logP parameters (optimal: MW ≤ 400; logP ≤ 4) [44].
-
Pfizer rule: the rule focuses on high logP > 3 and low topological polar surface area (TPSA) < 75 factors [45].
From Table 4, we can conclude that (i) the two derivatives 22a and 23a agree with the requirements of the Lipinski rule but the other two derivatives 22b and 23b do not match with the Lipinski rule, (ii) all Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) fulfil the conditions of the Pfizer rule and do not obey the GSK rule.

2.3.3. Medicinal Chemistry

Medicinal chemistry of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) was predicted using the ADMETlab 2.0 website https://admetmesh.scbdd.com/ (accessed on 11 August 2023).
Medicinal chemistry included the synthetic accessibility score (SA score) and the natural product-likeness score (NP score). Detailed information about the medicinal chemistry of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) can be seen in Table 4.
The synthetic accessibility score (SA score) is designed to estimate the ease of synthesis of drug-like molecules. The SA score ranges from 1 to 10. If the SA score is 1, the compound is easy to synthesize. But, if the SA score is 10 this compound is very difficult to synthesize [46]. According to this rule, the synthetic accessibility score of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) is in the range between 2.8 and 3.0, thus this series is easy to synthesize.
The natural product-likeness score (NP score) is a valuable measure that can help to guide the innovation of new molecules. The NP score ranges from −5 to 5. The higher the score is, the higher the probability that the molecule is like a natural product [47]. According to the rule of the natural product-likeness score, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) are similar and like a natural product as the NP score is between −1.4 and −0.9.

2.3.4. Molecular Lipophilicity Potential (MLP)

The molecular lipophilicity potential (MLP) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) was generated using the Molinspiration website https://www.molinspiration.com/cgi-bin/galaxy (accessed on 13 August 2023).
Molecular lipophilicity potential (MLP) on the molecular surface indicates which parts of the surface are hydrophobic and which are hydrophilic. MLP is calculated from atomic hydrophobicity contributions. The most lipophilic area is marked by a blue color, the intermediate lipophilic area has a pink color, the most hydrophilic area has a yellow color, and the intermediate hydrophilic area has a green color [48]. Figure 6 shows the molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b.

2.3.5. Molecular Polar Surface Area (PSA)

The molecular polar surface area (PSA) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) was generated using the Molinspiration website https://www.molinspiration.com/cgi-bin/galaxy (accessed on 13 August 2023).
Molecular polar surface area (PSA) is a very useful parameter for the prediction of drug transport properties. Polar surface area is defined as a sum of surfaces of polar atoms (usually oxygens, nitrogen, and attached hydrogens) in a molecule and it is highlighted by a red color. The non-polar surface area is indicated by a gray-white color [48]. Figure 7 shows the molecular polar surface area (PSA) of the derivatives 22a, b and 23a, b.

3. Materials and Methods

3.1. Chemistry

5-Amino-1H-pyrazoles-4-carboxamides 19a, b [36] and Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) [37] were prepared according to the method described in our work.
The spectral data of 5-aminopyrazoles 19a, b and the target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b), are listed in the Supplementary Material.

3.2. In Vitro Biological Activities

Antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were estimated according to the reported methods in the literature [38,39,40] (see Supplementary Material).

4. Conclusions

In this current manuscript, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were synthesized for evaluation of their in vitro antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The result of in vitro biological activities studies of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) exhibited that the compound 22b displayed significant antioxidant (TAC  = 42.47 ± 0.09 mg gallic acid/gm, IRP = 24.02 ± 0.05 µg/mL, DPPH (IC50) = 13.20 ± 0.03 µg/mL, and ABTS (%) = 35.11 ± 0.08), anti-diabetic (α-amylase inhibition% = 36.06 ± 0.08), and anti-Alzheimer’s (ACE% = 20.71 ± 0.05) activities, while the compound 23a displayed significant anti-arthritic activity (the protein denaturation inhibition% = 22.56 ± 0.05 and inhibition of proteinase% = 20.71 ± 0.05). Additionally, the in silico predicted bioinformatics analysis of the target derivatives (22a, b and 23a, b) revealed that: (i) the compounds (22a, b and 23a, b) may be orally bioavailable (physicochemical properties analysis). (ii) The two derivatives 22a and 23a fulfil the requirements of the Lipinski rule (drug-likeness analysis). (iii) All Schiff bases bearing pyrazole scaffold fulfil the conditions of the Pfizer rule (drug-likeness analysis). (iv) All Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) are easy to synthesize and like a natural product (medicinal chemistry analysis). Furthermore, molecular lipophilicity potential (MLP) and molecular polar surface area (PSA) studies were performed. These preliminary results of antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic activities of Schiff bases bearing pyrazole scaffold with in silico bioinformatics analysis could provide excellent models that may guide the discovery of multi-target drugs. In the future, biological activities studies will extend to other structures based on the Schiff bases bearing pyrazole scaffold in the hope of discovering effective and multi-target drugs.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28207125/s1, Spectral data of compounds (19a, b, 22a, b, and 23a, b) and biological methods.

Author Contributions

A.S.H. formulated the research idea; A.S.H., H.M.A., A.A.A., M.A.A.-O., A.J.O. and A.A.Z. carried out the experiments, interpreted the data, and performed the bioinformatics studies; W.M.A. performed the biological evaluation. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by King Saud University, Riyadh, Saudi Arabia through Researchers Supporting Project No. (RSPD2023R852).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are grateful to King Saud University, Riyadh, Saudi Arabia for funding the work through Researchers Supporting Project No. (RSPD2023R852).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Figure 1. Illustration of the relationship between diverse diseases (diabetes mellitus, Alzheimer, arthritis, and free radicals).
Figure 1. Illustration of the relationship between diverse diseases (diabetes mellitus, Alzheimer, arthritis, and free radicals).
Molecules 28 07125 g001
Figure 2. The pharmacological activities of Schiff bases 14, the pyrazole scaffold 59, and Schiff bases bearing pyrazole scaffold 1013.
Figure 2. The pharmacological activities of Schiff bases 14, the pyrazole scaffold 59, and Schiff bases bearing pyrazole scaffold 1013.
Molecules 28 07125 g002
Figure 3. The rationale and the studies of the target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Figure 3. The rationale and the studies of the target compounds, Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Molecules 28 07125 g003
Scheme 1. Synthesis of 5-aminopyrazoles 19a, b.
Scheme 1. Synthesis of 5-aminopyrazoles 19a, b.
Molecules 28 07125 sch001
Scheme 2. Synthesis of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Scheme 2. Synthesis of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Molecules 28 07125 sch002
Figure 4. The most potent derivatives 22b and 23a.
Figure 4. The most potent derivatives 22b and 23a.
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Figure 5. The bioavailability radar of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Figure 5. The bioavailability radar of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
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Figure 6. The molecular lipophilicity potential (MLP) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Figure 6. The molecular lipophilicity potential (MLP) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
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Figure 7. The molecular polar surface area (PSA) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Figure 7. The molecular polar surface area (PSA) of all the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Molecules 28 07125 g007aMolecules 28 07125 g007b
Table 1. The antioxidant activities of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Table 1. The antioxidant activities of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
DerivativesAntioxidant ActivityScavenging Activity
TAC
(mg Gallic Acid/gm)
IRP
(µg/mL)
DPPH
(IC50 µg/mL)
ABTS
(%)
22a34.75 ± 0.0819.65 ± 0.0416.22 ± 0.0428.73 ± 0.06
22b42.47 ± 0.09 *24.02 ± 0.05 *13.20 ± 0.03 *35.11 ± 0.08 *
23a36.85 ± 0.0820.84 ± 0.0515.21 ± 0.0330.46 ± 0.07
23b34.56 ± 0.0819.54 ± 0.0416.13 ± 0.0428.56 ± 0.06
STD--4.05 ± 0.0139.09 ± 0.09
Ascorbic Acid
* denotes the most effective compound. Values were calculated from three replicates and expressed as mean ± SE.
Table 2. The anti-diabetic, anti-Alzheimer’s, and anti-arthritic activities of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Table 2. The anti-diabetic, anti-Alzheimer’s, and anti-arthritic activities of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
DerivativesAnti-Diabetic ActivityAnti-Alzheimer’s ActivityAnti-Arthritic
Activity
α-Amylase Inhibition (%)Acetylcholinesterase
(ACE) Inhibition (%)
Proteinase Denaturation (%)Inhibition of Proteinase (%)
22a29.50 ± 0.0616.95 ± 0.0418.45 ± 0.0416.95 ± 0.04
22b36.06 ± 0.08 *20.71 ± 0.05 *19.57 ± 0.0417.97 ± 0.04
23a31.28 ± 0.0717.97 ± 0.0422.56 ± 0.05 *20.71 ± 0.05 *
23b29.34 ± 0.0616.85 ± 0.0418.35 ± 0.0416.85 ± 0.04
STD69.11 ± 0.15-49.33 ± 0.1141.88 ± 0.09
Acarbose Diclofenac Sodium
* denotes the most effective compound. Values were calculated from three replicates and expressed as mean ± SE
Table 3. The physicochemical properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Table 3. The physicochemical properties of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Derivatives22a22b23a23b
Molecular Weight (MW)471.190505.150490.120524.080
Volume479.897495.108468.876484.087
Density0.9821.0201.0451.083
nHA991010
nHD3333
nRot9988
nRing4444
MaxRing6666
nHet9101112
fChar0000
nRig26262727
Flexibility0.3460.3460.2960.296
Stereocenters0000
TPSA113.090113.090137.770137.770
logS−6.608−7.121−6.434−6.807
logP4.4215.1904.7115.455
logD7.43.7833.9103.9153.807
Table 4. The drug-likeness and medicinal chemistry of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Table 4. The drug-likeness and medicinal chemistry of the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
Derivatives22a22b23a23b
Molecular Weight (MW)471.190505.150490.120524.080
nHA991010
nHD3333
TPSA113.090113.090137.770137.770
logP4.4215.1904.7115.455
Lipinski RuleAcceptedRejectedAcceptedRejected
GSK RuleRejectedRejectedRejectedRejected
Pfizer RuleAcceptedAcceptedAcceptedAccepted
SA Score2.8862.9282.9863.027
NP Score−0.903−1.033−1.395−1.448
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Alkahtani, H.M.; Almehizia, A.A.; Al-Omar, M.A.; Obaidullah, A.J.; Zen, A.A.; Hassan, A.S.; Aboulthana, W.M. In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic. Molecules 2023, 28, 7125. https://doi.org/10.3390/molecules28207125

AMA Style

Alkahtani HM, Almehizia AA, Al-Omar MA, Obaidullah AJ, Zen AA, Hassan AS, Aboulthana WM. In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic. Molecules. 2023; 28(20):7125. https://doi.org/10.3390/molecules28207125

Chicago/Turabian Style

Alkahtani, Hamad M., Abdulrahman A. Almehizia, Mohamed A. Al-Omar, Ahmad J. Obaidullah, Amer A. Zen, Ashraf S. Hassan, and Wael M. Aboulthana. 2023. "In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic" Molecules 28, no. 20: 7125. https://doi.org/10.3390/molecules28207125

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