Bis-coumarins; non-cytotoxic selective urease inhibitors and antiglycation agents
Graphical abstract
Introduction
Bis-coumarins are biologically active pharmacophores, initially isolated from natural sources [1], [2]. Several biological activities are associated with bis-coumarins, such as α-glucosidase [3], urease [4], nucleotide pyrophosphatases-1 [5], and DNA polymerase β-lyase inhibitory activities [6]. Bis-coumarins are also reported to possess anticoagulant, and hemorrhagic properties [7]. However, there is still a need to explore this class for a wide spectrum of pharmacological activities.
Urease (amidohydrolase EC 3.5.1.5) is a metalloenzyme, contains nickel in its active site. It catalyzes the hydrolysis of urea into carbon dioxide and ammonia [8], [9]. This enzyme synthesizes by numerous plants, animals, bacteria, and other organisms [10]. Hyperactivity of urease is harmful to human and animal health, as well as for the agricultural sector. Urease is a key virulence in the pathogenesis of urolithiasis, urinary catheter encrustation, pyelonephritis, hepatic coma, and hepatic encephalopathy [11], [12]. It also participates in the pathologies caused by ureolytic bacteria Helicobacter pylori (HP). It facilitates bacteria to survive in stomach at acidic pH during initial colonization. Therefore, it plays an important role in the pathologies of ulcers (gastric and peptic), and cancer [13], [14], [15], [16]. In the agriculture sector, hyperactivity of urease leads to considerable economic and environmental damage by liberating aberrantly large quantities of ammonia into the atmosphere, during the process of urea fertilization [17]. Therefore, it is important to develop strategies based on urease inhibition to solve the problems caused by urease producing bacteria.
Glycation is a non-enzymatic reaction in which reducing sugars non-enzymatically bind with the amino terminal of proteins via a nucleophilic addition reaction, ultimately giving rise to advanced glycation end products (AGEs). Haemoglobin, serum albumin, collagen, elastin, and crystalline are common proteins that undergo glycation. Changes in their structures and functions lead to different abnormalities such as atherosclerosis, neuropathy, diabetic retinopathy, diabetic nephropathy, etc. This process is cumulatively called glycation stress [18], [19]. In this process, reactive intermediates such as methylglyoxal (MG) are more prone to bind with amino groups as compared to their carbohydrate precursors. Eighty percent (80%) of blood proteins is serum albumin, which is more likely to be glycated [20]. As a result of complex rearrangements, substitution, and addition reactions of glycated proteins, AGEs are produced in the body which change the functions of proteins, and accumulate with time in different tissues [21], [22], [23]. Many late diabetic complications, such as retinopathy, nephropathy, cataracts, atherosclerosis, and osteoporosis are due to the glycation of vital proteins, and accumulation of AGEs [24]. The inhibition of glycation process plays a pivotal role in the prevention of many late diabetic complications. Therefore, it is important to find inhibitors for glycation.
Bis-coumarins have not yet been reported for their antiglycation activity. Fig. 1 showed that chromone ring, a positional isomer of coumarin, is the main scaffold of rutin which encouraged us to evaluate the compounds 1–44 for their antiglycation activity. Furthermore, we have previously reported bis-coumarins for urease inhibitory activity [4]. New members of this series were thus evaluated to identify more potent urease inhibitors [Fig. 1]. In brief, forty-four derivatives were synthesized and evaluated for their urease inhibitory, and antiglycation activities. After knowing the selective potential of compounds, cytotoxicity was also checked. To the best of our knowledge, except compounds 6, 14, 16, 17, 19, 20, 23–26, 28, and 30–32 [25], [26], [27], [28], [29], the rest of the compounds were identified as new.
Section snippets
Chemistry
Bis-coumarin derivatives 1–44 were synthesized by reacting 6-fluoro-4-hydroxy, 4-hydroxy, and 6-chloro-4-hydroxy coumarins with a variety of benzaldehydes in the presence of tetraethylammonium bromide (TEAB) as a catalyst. Reactions were performed in distilled water (Scheme 1) and checked periodically by TLC analysis. Precipitates of products were obtained in good yields (Table 1). Compounds were structurally identified by various spectroscopic analyses such as 1H- and 13C NMR as well as FAB-,
Conclusion
Synthetic bis-coumarins 1–44 were evaluated for their urease inhibitory and antiglycation activities. Seven derivatives 4, 8–10, 14, 34, and 40 showed selective urease inhibition, whereas, twelve analogs 2, 11–13, 16, 17, 19–22, 35, 37, and 42 demonstrated antiglycation potential. Only compound 17 showed dual inhibition. All compounds were largely found to be non-cytotoxic. Newly identified compounds, based on bis-coumarin scaffold, may serve as leads for future research for more powerful,
Materials and methods
Thin layer chromatography (TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel 60 F-254, 0.20 mm, Merck, Darmstadt, Germany). Chromatograms were visualized by using a handhold UV lamp at 254, and 365 nm or placing in iodine vapors. Fast atom bombardement mass spectra (FAB MS) were recorded on a Finnigan MAT-311A (Germany) (70 eV) spectrometers, electrospray ionization mass spectra (ESI-MS, HRESI-MS) were recorded on a QSTAR XL LCMS-MS, and ABSciex (Germany) (50 kV) mass
Acknowledgement
The authors are thankful to the Higher Education Commission (HEC), Pakistan, for providing financial support under “National Research Program for Universities”, for Project No. 20-1910. One of us (Arsalan Nizamani) also acknowledges Higher Education Commission, Pakistan, for financial support through “Indigenous 5000 Scholarship Programme Batch-VII”.
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