Abstract
A series of barbiturates derivatives synthesized and screened for different set of bioassays are described. The molecular structures of compounds 5a, 5d, and 5f were solved by single-crystal X-ray diffraction techniques. The results of bioassay show that compounds 4a, 4b, 4c, 4d, 4e, 4f, and 4g are potent antioxidants in comparison to the tested standards, butylated hydroxytoluene (BHT), and -acetylcysteine. Compounds 4a–4e () and 4g () were more potent antioxidants than the standard (BHT, ). The enzyme inhibition potential of these compounds was also evaluated, in vitro, against thymidine phosphorylase, -glucosidase, and -glucuronidase enzymes. Compounds 4c, 4h, , 4p, 4q, 5f, and 5m were found to be potent -glucosidase inhibitors and showed more activity than the standard drug acarbose, whereas compounds 4v, and 5h were found to be potent thymidine phosphorylase inhibitors, more active than the standard drug, 7-deazaxanthine. All barbiturates derivatives (4a–4x, 4z, and 5a–5m) were found to be noncytotoxic against human prostate (PC-3), Henrietta Lacks cervical (HeLa) and Michigan Cancer Foundation-7 breast (MCF-7) cancer cell lines, and 3T3 normal fibroblast cell line, except 4y which was cytotoxic against all the cell lines.
1. Introduction
Derivatives of 1,3-dimethylbarbituric acid including pyrimidine-2,4,6-trione (PYT) heterocycles play an important role in the pharmaceutical chemistry [1, 2]. Barbituric acid and its derivatives are well known as hypotensive, antibacterial, and antisclerotic, hypnotic, sedative, anticonvulsant, antispasmodic, anticancer, matrix metalloproteinase inhibitors, anticonvulsants, and anti-inflammatory and anxiolytic agents, as well as being used in local anesthetic drugs [2–9]. Barbituric acid derivatives are also known for their use as clinical drugs, such as Seconal, Veronal, phenobarbital, bucolome, and sodium pentothal (Figure 1, 1–5) [10–13]. The interesting mechanism of action of barbital and phenobarbital against epilepsy made them attractive targets for medicinal chemists. They have also been investigated as anticancer and anti-AIDS agents [14]. Reactive oxygen species (ROS) are oxygen-centered free radicals such as reactive oxygen species (ROS) which are peroxyls (ROO•), superoxides (), hydroxyls (HO•), alkoxyls (RO•), and nitric oxides (NO•) [15], while hypochlorous acid (HOCl), hydrogen peroxide (H2O2), and singlet oxygen (O2) are classified as nonradical ROS. The ROS may react in various environments [15]. However overproduction of ROS species has been linked to cell membrane damage, protein and enzyme modifications, and DNA damage within the body [16]. These types of changes accelerate aging and play a causative role in a variety of degenerative diseases, such as cancers, atherosclerosis, brain disfunction, inflammation, shock, and heart diseases. Recently Barakat et al. [17] have synthesized some novel salts of Michael adduct derived from PYT and evaluated them for NO (nitric oxide) scavenging activity. Compound 10 was found to possess several hundredfold more activity against nitric oxide radical (IC50 values of μM) than the standard drug ascorbic acid (IC50 = μM).
Because of the important biological activities, PYT is widely used as a synthon in the design of antitumor agents. It has a high efficacy to form hydrogen bonding with drug targets (6–9, Figure 1). Singh et al. have reported the activity of a series of new N-benzyl indole-pyrimidine-2,4,6-trione hybrids against a panel of 60 human tumor cell lines. Several of these analogs were also found to be inhibitors of DNA repair and replication stress response polymerases [18].
The discovery and development of effective antioxidants capable of supplementing body’s antioxidant system is an important area of health care research. Similarly research efforts are focused on the identification of effective and safe inhibitors of -glucosidase as potential antidiabetic agents.
The focus in recent years is on the development of resource-efficient, environmentally benign, and sustainable chemistry practices. In continuation of our work in this field, we describe here the synthesis of a series of previously reported [17, 19, 20] and new PYT adducts. These compounds were evaluated for their antioxidant activity by using DDPH scavenging assay, as well as for in vitro enzyme inhibition activities against alpha-glucosidase, thymidine phosphorylase, and -glucuronidase enzymes.
2. Materials and Methods
The chemical reagents used for the preparation of the target compounds were commercially available and used without further purification. 1H-NMR and 13C-NMR were measured using Bruker Avance AV-600 NMR spectrometer, MS were carried out with a Jeol, JMS-600 H instrument, and single-crystal X-ray diffraction was collected using a Bruker SMART APEX II CCD diffractometer.
2.1. General Procedure for Aldol Condensation Michael Addition for the Synthesis of 4 and 5 (GP1)
A mixture of aldehyde 3 (1.5 mmol) and 1 and 2 (3 mmol) as well as Et2NH (1.5 mmol, 155 μL) in 3 mL of degassed H2O (bubbling nitrogen through the water) was stirred at room temperature for 1–5 h until TLC showed complete disappearance of the reactants. The precipitate was removed by filtration and washed with ether ( mL). The solid product was dried to afford pure products 4 and 5.
The full characterization of the synthesized compounds 4 and 5 and the X-ray crystal data of 5a, 5d, and 5f can be seen in the Supplementary Materials (see supplementary materials available online at http://dx.doi.org/10.1155/2016/8517243).
2.2. Biological Activity
The samples of the synthesized compound were screened against DPPH radical, -glucuronidase inhibition assay, thymidine phosphorylase inhibition assay, and -glucosidase inhibition assay and full methods descriptions are provided in Supplementary Materials.
3. Results and Discussion
3.1. Chemistry
We have been focusing on the development of highly expedient methods for the synthesis of diverse heterocyclic compounds of biological importance via one-pot multicomponent reactions (MCRs) and avoiding organic solvents in organic synthesis [17, 19, 20]. This had led to the development of several efficient, environmentally benign, clean, and economical process technology (Green Chemistry Concepts). In current reaction strategy, equimolar amounts of barbituric acid (1) and dimedone (2) with aldehyde (3) in the presence of aqueous diethylamine medium at RT yielded salts of PYT adducts 4a–4y and 5a–5m were obtained in quantitative yields by simple filtration [17–20]. Products 4s, 4t, and 5g were identified as new products (Scheme 1).
3.2. X-Ray Diffraction
The molecular structures of compounds 5a, 5d, and 5f were unambiguously deduced by single-crystal X-ray diffraction technique (Figure 2). The crystals of the synthesized molecules 5a, 5d, and 5f were grown by slow diffusion of diethyl ether solution of pure samples 5a, 5d, and 5f in DCM/EtOH at room temperature followed by allowing standing for 24 h. The structures were resolved by direct methods by using the SHELXL97 program [21, 22] in the SHELXTL-plus package and refined by a full-matrix least-squares procedure on using SHELXS97. Diffraction data were collected on a Bruker APEX-II CCD diffractometer (Bruker AXS GmbH). The crystal structure and refinement data of compounds 5a, 5d, and 5f are listed in Table 1. The final atomic coordinates for all atoms and complete listing of bond distance and angles are presented in supplementary information. ORTEP drawings of final X-ray model of compounds 5a, 5d, and 5f with the atomic numbering scheme are presented in Figure 2, while crystal packing presentation of compounds 5a, 5d, and 5f is shown in Figure 3.
Compound 5a crystallizes in orthorhombic crystal system in a space group of P212121; on the other hand, compounds 5d and 5f crystalize in monoclinic crystal system in a space group of P21/n. It was observed that the compound 5a has hydrogen bonding between the C5-O2⋯H⋯O4-C13, while compounds 5d and 5f exist only in the enol form. There are two strong intramolecular hydrogen bonds on compound 5a between O4—H1O4⋯O2 and N2—H2N2⋯O1, while compounds 5d and 5f have no intramolecular hydrogen bonding. The crystal structures of the tested compounds 5a, 5d, and 5f were formed by different hydrogen bonds between the molecules and diethyl amine and water solvent molecules in case of 5a to form network structures. Crystallographic data for the solved structures 5a, 5d, and 5f were deposited to the Cambridge Crystallographic Data Center as supplementary publication numbers CCDC-1444058, CCDC-1443783, and CCDC-1444050, respectively, which can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
3.3. Biological Activity Evaluation
All synthesized diethyl ammonium salts of barbiturates having bis(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) (4a–4h), bis(6-hydroxypyrimidine-2,4(1H,3H)-dione (4i–4l), and (2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate (4m–4z) as well as bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-ene) (5a–5m) as basic nuclei were screened for their antioxidant potential in vitro by using DPPH radical scavenging assay and cytotoxicity against PC-3, HeLa, and MCF-7 cancer cell lines and 3T3 normal fibroblast cell lines. These derivatives 4a–4z and 5a–5m were also evaluated for in vitro enzyme inhibition activities against -glucosidase, thymidine phosphorylase, and -glucuronidase enzymes. The results are summarized in Table 2.
3.3.1. Antioxidant Activity (DPPH Radical Scavenging Assay)
Among series of compounds (4a–4h) having bis(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) ring as basic nucleus, compounds 4a (IC50 = μM), 4b (IC50 = μM), 4c (IC50 = μM), 4d (IC50 = μM), 4e (IC50 = μM), 4f (IC50 = μM), and 4g (IC50 = μM) were found to be potent antioxidants in comparison to the standards BHT (IC50 = μM) and N-acetylcysteine (IC50 = μM). Compounds 4a–4e (IC50 = μM) were found to be more active compared to the standard BHT (IC50 = μM). The meta-bromo-substituted phenyl ring containing compound 4e (IC50 = μM) was the most potent member of the series (4a–4e), followed by the para-methyl-substituted phenyl ring containing compound 4g (IC50 = μM). A gradual decrease in activity was observed for compounds 4c (IC50 = μM) and 4a (IC50 = μM) having para-nitro- and para-aldehyde-substituted phenyl ring attached to central bis(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) ring. A decrease in DPPH radical scavenging activity was due to positional effect of methyl substituent on phenyl ring which was observed for compound 4b (IC50 = μM) having meta-substituted phenyl ring instead of para-methyl-substituted phenyl ring (4g, IC50 = μM). The electron donating para-hydroxyl-substituted phenyl ring containing compound 4f (IC50 = μM) was found to be a last active member of the series. However, a considerable increase in activity was observed for compound 4d (IC50 = μM) having a para-methoxy group instead of hydroxyl functionality on phenyl ring, whereas naphthalene ring containing barbiturate 4h (IC50 = μM) was also found to be a weak antioxidant agent against DPPH radicals.
Among second series of the tested compounds 4i–4l having bis(6-hydroxypyrimidine-2,4(1H,3H)-dione as backbone, compounds having para-methyl- (4i, IC50 = μM), para-chloro- (4j, IC50 = μM), and para-methoxy- (4l, IC50 = μM) substituted phenyl ring attached to the central bis(6-hydroxypyrimidine-2,4(1H,3H)-dione) showed better antioxidant activity as compared to BHT (IC50 = μM) and N-acetylcysteine (IC50 = μM), whereas naphthalene containing compound 4l was found to be inactive.
(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate ring containing compounds 4m–4z were also evaluated for their antioxidant potential in vitro in DPPH radical scavenging assay. These compounds were found to be significant to weak inhibitors of free radicals (IC50 = μM) except compounds 4m–4r and 4y which were found to be inactive.
Similarly bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-ene) (5a–5h) and 4-((6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) (6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl) (5i–5k) rings containing compounds were also evaluated for their antioxidant potential by using DPPH radical scavenging assay. Para-bromo-substituted phenyl ring containing compound 5k (IC50 = μM) was found as a potent antioxidant agent against the tested standards BHT (IC50 = μM). The compound showed similar antioxidant potential as BHT and showed a significant antioxidant agent against N-acetyl cysteine (IC50 = μM). The gradual and drastic decrease in activity was for compounds 5l (IC50 = μM), 5g (IC50 = μM), 5e (IC50 = μM), and 5a (IC50 = μM) having para-methyl-, para-aldehyde-, ortho-chloro-, and ortho-nitro-substituted phenyl rings attached to the central barbiturate moieties. Compounds 5b–5d, 5f, and 5h–5j were found to be inactive.
On the basis of the observed antioxidant abilities of the above five different series of pyridinium adducts, it was concluded that bis(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) ring containing compounds 4a–4h are the most active one. The activity may be due to the methyl substituted nitrogen atoms of the tetrahydropyrimidine rings that facilitate the electronic conjugation within the ring. However, the variation of antioxidant properties within the most important series is may be due to the presence of electron donating (-OH (4f), -OCH3 (4d), and -CH3 (4b, 4g)), electron withdrawing (-NO2 (4a) and -CHO (4c)), and halogen (-Br (4e)) substituents on the phenyl ring attached to the bis(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) moiety. However, detailed studies are required to study the mechanism of action of these compounds.
3.3.2. Cytotoxic Activity
All synthesized diethyl ammonium salts of barbiturates (4a–4z and 5a–5m) were evaluated for their in vitro cytotoxicity against PC-3, HeLa, MCF-7 cancer, and 3T3 normal cell lines. All compounds were found to be noncytotoxic against PC-3, HeLa, MCF-7 cancer, and 3T3 cell lines except dichloro-substituted (2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate ring containing compounds 4y, which was found to be significantly toxic against all the cell lines (PC3, IC50 = μM, HeLa, IC50 = μM, MCF-7, IC50 = μM, and 3T3, IC50 = μM). Doxorubicin was used as a standard drug to compare the activities against PC3 (IC50 = μM), HeLa (IC50 = μM), and MCF-3 (IC50 = μM) cancer cell lines, while cycloheximide (IC50 = μM) was used as a standard-in 3T3 cell line (Table 2).
3.3.3. α-Glucosidase Inhibition Activity
Synthesized diethyl ammonium salts of barbiturates, 4a–4z and 5a–5m, were also evaluated for their in vitro -glucosidase inhibition activity, in comparison to the standard drug, acarbose (IC50 = μM). Among dimethyl ammonium salts (4a–4h), nitro-substituted phenyl ring containing 4c (IC50 = μM) and naphthalene ring containing 4h (IC50 = .92 μM) were found to be potent inhibitors of α-glucosidase enzyme and showed more activity than acarbose (IC50 = μM). All other compounds were found to be inactive.
Among diethyl ammonium salts having (2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate ring (4m–4z), para-OCH3- (40, IC50 = μM), para-chloro- (4p, IC50 = μM), para-bromo- (4q, IC50 = μM), and meta-bromo- (4r, IC50 = μM) substituted phenyl ring containing pyridinium adducts were found to be potent α-glucosidase inhibitors and showed more activity than standard acarbose (IC50 = μM). Other members of the series (4m-4n and 4s–4z) were found to be inactive. The results showed the substitution effects of various functionalities of phenyl ring on the potential activity of tested series. The para-bromo-substituted phenyl ring containing compound 4q (IC50 = μM) showed more activity than tested standard. However, the replacement of bromo group with that of methyl, N,N-dimethyl, hydroxyl, and aldehyde functionalities resulted in complete loss of activity as observed in compounds 4n, 4t, 4v, and 4x, respectively. The presence of ortho-nitro-, ortho-choloro-, and para-choloro-substituted phenyl ring also contributed towards inactivity, as observed for compounds 4t, 4w, and 4y.
Similarly bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-ene) ring containing diethyl ammonium pyridinium salts (5a–5h) were also evaluated for their in vitro α-glucosidase enzyme inhibition activity. The series nitro-substituted phenyl ring containing 5f was found to be the only potent α-glucosidase inhibitor. All other compounds (5a–5e and 5g-5h) were found to be inactive.
Among series of diethylaminium salts of pyridinium adducts (5i–5m) having 4-((6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) (6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl) central moiety attached with substituted phenyl ring, the benzaldehyde containing 5m (IC50 = 453.4 ± 4.2 μM) was found to be the only potent inhibitor compound in comparison to against the standard drug acarbose (IC50 = μM). All other compounds were found to be inactive. The results are summarized in Table 2.
3.3.4. Thymidine Phosphorylase Inhibition Activity
Five different series of diethyamonium salts of barbiturates, 4a–4g, 4i–4k, 4m–4z, 5a–5h, and 5i–5m, were also evaluated for their in vitro thymidine phosphorylase inhibition. 7-Deazaxanthine was used as a standard inhibitor (IC50 = μM). Phenol and naphthalene rings substituted (2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate moiety containing compounds 4v (IC50 = .20 μM) and 4z (IC50 = .50 μM) were found to be the potent thymidine phosphorylase inhibitors. However, a drastic decrease in activity was observed when para-hydroxy group on phenyl ring was replaced with methyl (4n, IC50 = μM), chloro (4n, IC50 = μM), bromo (4q, IC50 = μM), and aldehyde (4x, IC50 = μM) groups, whereas the compounds 4o, 4s, 4t, 4w, and 4y have para-methoxy-, ortho-nitro-, ortho-N,N-dimethyl amine-, ortho-, para-dichloro-, and ortho-ortho-dichloro-substituted phenyl ring, respectively.
Among series of compounds (5a–5h) having bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-ene) ring as central moiety, electron donating hydroxy- and methoxy-substituted phenyl ring containing compounds 5h (IC50 = .6 μM) and 5d (IC50 = μM), respectively, were found as potent inhibitors of thymidine phosphorylase enzyme against the tested standard 7-deazaxanthine which was (IC50 = μM) used as standard. Again a drastic decrease in activity was observed for compounds 5b (IC50 = μM), 5c (IC50 = μM), and 5g (IC50 = μM) having meta-methyl-, ortho-methyl-, and para-aldehyde-substituted benzene ring respectively, instead of para-hydroxyl phenyl ring. The replacement of ortho-methyl with chloro-group makes the compound 5e completely inactive. Similarly the replacement of electron donating para-hydroxy-group of phenyl ring with electron withdrawing nitro-functionality also contributed towards inactivity of compound, as observed for 5f. Phenol substituted bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-ene) ring containing 5h (IC50 = 56.9 ± 1.6 μM) was found to be the potent thymidine phosphorylase inhibitors.
All members of the series of diethylaminium salts of pyridinium adducts (5i–5m) having 4-((6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) (6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl) central moiety attached with substituted phenyl ring were found to be weak inhibitors of thymidine phosphorylase enzyme against the tested standard compound 7-deazaxanthine (IC50 = μM) with IC50 values μM, μM, μM, and μM for 5j, 5k, 5l, and 5m, respectively, whereas para-chloro-substituted phenyl ring containing compound 5i was found to be inactive. The results are summarized in Table 1.
3.3.5. β-Glucuronidase Inhibition Activity
Compounds 4a–4g, 4i–4k, 4m–4z, 5a–5h, and 5i–5m were also evaluated for their in vitro β-glucuronidase inhibitory activity by using D-saccharic acid 1,4-lactone as standard inhibitor (IC50 = μM). Compounds 4a (IC50 = .01 μM), 4c (IC50 = .1 μM), 4e (IC50 = .42 μM), 4o (IC50 = μM), 4q (IC50 = .03 μM), 4r (IC50 = .4 μM), 4w (IC50 = .24 μM), 5f (IC50 = .5 μM), 5i (IC50 = .4 μM), and 5l (IC50 = .0 μM) showed very weak β-glucuronidase inhibition potential, whereas pyridinium adducts 4a–4c, 4e, 4g–4j, 4l, 4o, 4s-4t, 4w, 4y, 5a, 5e-5f, and 5i were found to be inactive (Table 2).
3.4. Molecular Docking Studies
3.4.1. Binding Interactions of α-Glucosidase Enzyme
To define inhibitors interactions and their specificity, the docking study of the most active compound 4p against -glucosidase was carried out [23–25]. Ten different conformations of protein-ligand interactions were generated and the top ranked pose was selected to explore the binding interactions. In our docking study, we have observed two interactions with the active site residues of -glucosidase. The polar imidazole ring of His 239 showed hydrogen bond through its H atom with the lone pair of oxygen of the pyrimidinedione moiety of the compound, whereas Arg 312 formed hydrogen bond with the OH group of the same moiety of compound (Figure 4). The presence of polar and electron rich center in the form of pyrimidinedione and chlorobenzene groups of the compound was observed here as key factors for the interaction between compound and protein. A number of hydrogen bond donor and acceptor pairs with their suitable orientations were observed in the interaction pose. Furthermore, several hydrophobic interactions between the nonpolar active site residues and the compound 4p were also observed.
3.4.2. Binding Interactions of Thymidine Phosphorylase Enzyme
To explore the binding modes of these newly synthesized compounds in the active site of thymidine phosphorylase, the most active compound 4v was docked against this enzyme. The docking results showed that compound 4v well accommodated in the active site of thymidine phosphorylase (Figure 5). The active site residue Ala 206 established a hydrogen bond through its lone pair of oxygen with the active hydrogen of hydroxyl moiety of the pyrimidinedione group of the compound. However, the substituted phenolic group and the other electron rich centers of the pyrimidinedione showed poor behavior regarding interaction which may depend on the nature and orientation of the surrounding active site residues. Moreover, several weak hydrophobic interactions between the active site residues and the compound were also observed.
3.4.3. Binding Interaction of β-Glucuronidase Enzyme
The predicted binding mode of most active compound 4w against -glucuronidase showed that a hydrogen bond is formed between the lone pair of oxygen of cyclohexanedione component of the compound and imidazole hydrogen of the important active site residue, His 509. An arene-arene and arene-cation interaction was also observed between the pi electronic cloud of dichlorobenzene ring of compound and imidazole ring of His 509 (Figure 6). Besides hydrogen bonding and arene-arene interactions, several hydrophobic interactions between compound 4w and the active site residues were also observed. The pyrimidinedione moiety in this case was observed to be passive regarding interactions.
4. Conclusions
In conclusion, barbiturate salts were synthesized by one-pot multicomponent reactions via tandem Aldol/Michael addition reactions between barbituric acid and dimedone with aldehydes, mediated by aqueous diethylamine. The molecular structures of 5a, 5d, and 5f were deduced by single-crystal X-ray diffraction techniques. All of the synthesized compounds were evaluated for their antioxidant potential in vitro by using DPPH radical scavenging assay as well as enzyme inhibition activities against -glucosidase, thymidine phosphorylase, and -glucuronidase enzymes. Compounds 4a–4g (IC50 = μM) were found to be the potent antioxidants as compared to the standards, BHT (IC50 = μM), and N-acetylcysteine (IC50 = μM). Compound 4p (IC50 = μM) was found to be a potent -glucosidase inhibitor. Compound 4v (IC50 = μM) was found to be a potent thymidine phosphorylase inhibitor. Promising results indicate that these compounds need to be investigated as antioxidant agents to treat various associated oxidative disorders. Similarly their enzyme inhibitory potential can be reported on drug discovery program.
Competing Interests
The authors declare that there are no competing interests regarding the publication of this paper.
Authors’ Contributions
Assem Barakat, Hazem A. Ghabbour, Abdullah Mohammed Al-Majid, Qurat-ul-ain, Rehan Imad, Kulsoom Javaid, Nimra Naveed Shaikh, Sammer Yousuf, M. Iqbal Choudhary, and Abdul Wadood contributed equally to this work.
Acknowledgments
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this Research Group no. (RGP-257-1435-1436).
Supplementary Materials
The Supplementary Material file gives full characterization of the synthesized compounds, X-ray single crystals data, bioassays, and molecular docking studies.