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Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

ABSTRACT: Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (5a-5j) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals. All of the investigated compounds displayed a more powerful inhibitory profile than the reference agent, KH₂PO₄ particularly compound 5h and 5a exhibited strong inhibitory potential against ALP with IC₅₀ value of 0.365 ± 0.011 and 0.436 ± 0.057 µM respectively. In addition, Lineweaver-Burk plots revealed the non-competitive inhibition mode of the most powerful derivative i.e., 5h (ki value 0.5 µM). To investigate the putative binding mode of selective inhibitor interactions, molecular docking was performed. It is recommended that future research will focus on developing selective alkaline phosphatase inhibitors by modifying the structure of the 5h derivative.

SUBMITTER: Saeed A

PROVIDER: S-EPMC10088808 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

Saeed Aamer A Ashraf Saba S Aziz Mubashir M Channar Pervaiz Ali PA Ejaz Syeda Abida SA Fayyaz Ammara A Abbas Qamar Q Alasmary Fatmah Ali FA Karami Abdulnasser Mahmoud AM Tehzeeb Arfa A Mumtaz Amara A El-Seedi Hesham R HR

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 20230410 6

Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (<b>5a-5j</b>) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline p ...[more]

PMID: 37305207

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Project description:Tissue nonspecific alkaline phosphatase (TNAP) contributes to the production of adenosine by the kidney, and A1-receptor activation enhances renovascular responses to norepinephrine. Therefore, we hypothesized that TNAP regulates renovascular responsiveness to norepinephrine. In isolated, perfused rat kidneys, the TNAP inhibitor l-p-bromotetramisole (0.1 mmol/L) decreased renal venous levels of 5'-AMP (adenosine precursor) and adenosine by 61% (P<0.0384) and 62% (P=0.0013), respectively, at 1 hour into treatment and caused a 10-fold rightward shift of the concentration-response relationship to exogenous norepinephrine (P<0.0001). Similarly, 2 other TNAP inhibitors, levamisole (1 mmol/L) and 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (0.02 mmol/L), also right shifted the concentration-response relationship to norepinephrine. The ability of TNAP inhibition to blunt renovascular responses to norepinephrine was mostly prevented or reversed by restoring A1-adenosinergic tone with the A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (100 nmol/L). All 3 TNAP inhibitors also attenuated renovascular responses to renal sympathetic nerve stimulation, suggesting that TNAP inhibition attenuates renovascular responses to endogenous norepinephrine. In control propranolol-pretreated rats, acute infusions of norepinephrine (10 μg/kg/min) increased mean arterial blood pressure from 95±5 mm Hg to a peak of 169±4 mm Hg and renovascular resistance from 12±2 mm Hg/mL/min to a peak of 55±12 mm Hg/mL/min; however, in rats also treated with intravenous l-p-bromotetramisole (30 mg/kg), the pressor and renovascular effects of norepinephrine were significantly attenuated (blood pressure: basal and peak, 93±7 and 146±6 mm Hg, respectively; renovascular resistance: basal and peak, 13±2 and 29±5 mm Hg/mL/min, respectively). TNAP inhibitors attenuate renovascular and blood pressure responses to norepinephrine, suggesting that TNAP participates in the regulation of renal function and blood pressure.

Dataset Information

Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

Publications

Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

Similar Datasets

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