“…Recently, we have reported coumarinyl sulphonates derivatives as novel and potent inhibitors of h -TNAP and h -IAP 13 . In continuation of our efforts for searching the effective and selective inhibitors, herein we evaluated a series of 27 tricyclic-fused coumarin sulphonate derivatives 1a-za as inhibitors of APs which were already tested for their antiproliferative and anti-inflammatory activities 14–17 .…”
Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.
“…Recently, we have reported coumarinyl sulphonates derivatives as novel and potent inhibitors of h -TNAP and h -IAP 13 . In continuation of our efforts for searching the effective and selective inhibitors, herein we evaluated a series of 27 tricyclic-fused coumarin sulphonate derivatives 1a-za as inhibitors of APs which were already tested for their antiproliferative and anti-inflammatory activities 14–17 .…”
Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.
“…Thus, ethyl 4‐(1 H ‐indol‐3‐yl)butanoate ( 2 ) was obtained as brownish liquid (solid at refrigeration) . The second step was performed to convert this ethyl ester to respective carbohydrazide, 3 , by the nucleophillic hydrazine in the presence of an organic solvent like methanol and refluxed for 14 h. Thus, 4‐(1 H ‐indol‐3‐yl)butanohydrazide ( 3 ) was obtained as a light brown‐colored solid . The third step was a cyclization to form heterocyclic ring through reaction with CS 2 in a basic alcoholic medium.…”
Section: Resultsmentioning
confidence: 99%
“…The third step was a cyclization to form heterocyclic ring through reaction with CS 2 in a basic alcoholic medium. The resulting product was 5‐[3‐(1 H ‐indol‐3‐yl)‐propyl]‐1,3,4‐oxadiazole‐2‐thiol ( 4 ) having a mercapto group at its second carbon . In a parallel phase of reactions, different electrophiles were synthesized by reacting substituted anilines ( 5a–k ) with 4‐(chloromethyl)benzoyl chloride ( 6 ) to afford 4‐(chloromethyl)‐ N ‐(substituted‐phenyl)benzamides ( 7a–k ) .…”
Section: Resultsmentioning
confidence: 99%
“…A number of Alzheimer's disease patients have indicated considerable elevated TNAP activity in the hippocampus section of brain. TNAP can therefore be explored as a potential target for treatment of neurological disorders …”
Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide (3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k) with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.
Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphatecontaining physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019). K E Y W O R D S alkaline phosphatase, inhibitors, isoenzymes, structure-activity relationship
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