Abstract
Curcumin, a constituent of Curcuma longa, has shown numerous biological and pharmacological activities, including antidiabetic effects. Here, a novel series of curcumin analogues were synthesized and evaluated for in vitro inhibition of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which plays a key role in the onset and progression of diabetic complications. Biological activity studies showed that all the curcuminoids exhibited moderate to good AR inhibitory (ARI) activities compared with that of the quercetin standard. Importantly, compounds 8d, 8h, 9c, 9e, and 10g demonstrated promising ARI activities, with the 50% inhibitory concentration (IC50) values of 5.73, 5.95, 5.11, 5.78, and 5.10 µM, respectively. Four other compounds exhibited IC50 values in the range of 6.04–6.18 µM. Methyl and methoxy derivatives showed a remarkable ARI potential compared with that of other substitutions on the aromatic ring. Molecular docking experiments demonstrated that the most active curcuminoid (10g) was able to favorably bind in the active site of the AR enzyme. The potent ARI activities exhibited by the curcuminoids were attributed to their substitution patterns on the aromatic moiety, which may provide novel leads in the development of therapeutics for the treatment of diabetic complications.
Highlights
Diabetes mellitus (DM) is a complex metabolic disorder characterized by high blood glucose levels and the development of chronic complications, including neuropathy, nephropathy, retinopathy, and cataracts [1,2]
Melting points of the synthesized compounds were recorded in open glass capillaries using an electrical melting point apparatus and were not corrected; 1H nuclear magnetic resonance (NMR) spectra were recorded on a Mercury-VX 400 MHz NMR spectrometer (Varian, UK) at room temperature
All the synthesized curcumin analogs contain two identical aryl rings separated by an unsaturated five-carbon spacer with a single carbonyl, whereas some compounds have two different aryl rings (Table 1)
Summary
Diabetes mellitus (DM) is a complex metabolic disorder characterized by high blood glucose levels and the development of chronic complications, including neuropathy, nephropathy, retinopathy, and cataracts [1,2]. This disorder leads to kidney failure, heart attack, and stroke, which results in more than 50% of fatalities in diabetic patients [3,4]. The International Diabetes Federation (IDF) has reported that an estimated 425 million adults worldwide had DM in 2017, and predicted that almost. Recent advances in the understanding of DM pathology have revealed that the aldose reductase (AR; alditol:(nicotinamide adenine dinucleotide phosphate (NADP+) 1-oxidoreductase, EC 1.1.1.21)
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