Substituted phenyl[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetates/acetamides as alkaline phosphatase inhibitors: Synthesis, computational studies, enzyme inhibitory kinetics and DNA binding studies (original) (raw)
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RSC Advances, 2023
Heterocycles are a class of compounds that have been found to be potent inhibitors of alkaline phosphatase (AP), an enzyme that plays a critical role in various physiological processes such as bone metabolism, cell growth and differentiation, and has been linked to several diseases such as cancer and osteoporosis. AP is a widely distributed enzyme, and its inhibition has been considered as a therapeutic strategy for the treatment of these diseases. Heterocyclic compounds have been found to inhibit AP by binding to the active site of the enzyme, thereby inhibiting its activity. Heterocyclic compounds such as imidazoles, pyrazoles, and pyridines have been found to be potent AP inhibitors and have been studied as potential therapeutics for the treatment of cancer, osteoporosis, and other diseases. However, the development of more potent and selective inhibitors that can be used as therapeutics for the treatment of various diseases is an ongoing area of research. Additionally, the study of the mechanism of action of heterocyclic AP inhibitors is an ongoing area of research, which could lead to the identification of new targets and new therapeutic strategies. The enzyme known as AP has various physiological functions and is present in multiple tissues and organs throughout the body. This article presents an overview of the
European Journal of Medicinal Chemistry, 2013
A new series of structurally diverse chromone containing sulfonamides has been developed. Crystal structures of three representative compounds (2a, 3a and 4a) in the series are reported. All compounds were screened for their inhibitory potential against alkaline phosphatases (ALPs). Two main classes of ALP isozymes were selected for this study, the tissue non-specific alkaline phosphatase (TNALP) from bovine and porcine source and the tissue-specific intestinal alkaline phosphatases (IALPs) from bovine source. All sulfonamide compounds had a marked preference for IALP (K i , up to 0.01 AE 0.001 mM) over TNALPs. Kinetics studies of the compounds showed competitive mode of inhibition. Molecular docking studies were carried out in order to characterize the selective inhibition of the compounds. An additional interesting aspect of these chromone sulfonamides is their inhibitory activity against ecto-5 0-nucleotidase enzyme.
Differential effect of 4′-phenylchalcones on acid and alkaline phosphatases
Medicinal Chemistry Research, 2014
Acid phosphatase and alkaline phosphatase are used as diagnostic tool for the identification of various diseased conditions. It has been reported that low levels of acid phosphatase and elevated levels of alkaline phosphatase are present in different cancerous conditions. In vitro enzyme-related studies emphasize the potential of therapeutic uses of various compounds. In the present work, we report differential effect of 4 0-phenylchalcones on the activities of these two clinically significant enzymes. The data revealed that all the synthesized compounds were inhibitory to alkaline phosphatase compared to levamisole, whereas an activating effect has been observed on acid phosphatase. For example, compound, 1b, inhibited the alkaline phosphatase activity maximally up to 80 % at 1 9 10-3 M concentration, but activated the acid phosphatase up to 186 % at the same concentration. In addition, molecular modelling and docking of these compounds into alkaline phosphatase active site using iGemdock were performed in order to predict the affinity and orientation of the designed compounds at the active site and were compared with the established inhibitor levamisole.
Journal of cellular biochemistry, 2018
In the recent years, the role of alkaline phosphatase (AP) isozymes in the cause of neoplastic diseases such as breast, liver, renal and bone cancer has been confirmed and, thus they represent a novel target for the discovery of anticancer drugs. In this study different derivatives of thiazol-2-ylidene-benzamide were evaluated for their potential to inhibit alkaline phosphatase (AP) isozymes. Their anticancer potential was assessed using human breast cancer (MCF-7), bone-marrow cancer (K-562) and cervical cancer (HeLa) cell lines in comparison to normal cells from baby hamster kidney BHK-21. The results suggested that in comparison to other derivatives, compounds 2i, 2e and 2a showed more sensitivity towards human tissue non-specific alkaline phosphatase (h-TNAP). Among these, 2''-chloro-N-(3-(4'-fluorophenyl)-4-methylthiazol-2(3H)-ylidene) benzamide (2e) was found as the most potent and selective inhibitor for h-TNAP with an IC50 value of 0.079 ± 0.002 µM. Moreover, a s...
Archiv der Pharmazie, 2019
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 ki...
Journal of Medicinal Chemistry, 2009
We report the characterization and optimization of drug-like small molecule inhibitors of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for the regulation of extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) of a small molecule library led to the identification of arylsulfonamides as potent and selective inhibitors of TNAP. Critical structural requirements for activity were determined, and the compounds were subsequently profiled for in vitro activity and bioavailability parameters including metabolic stability and permeability. The plasma levels following subcutaneous administration of a member of the lead series in rat was determined, demonstrating the potential of these TNAP inhibitors as systemically active therapeutic agents to target various diseases involving soft tissue calcification. A representative member of the series was also characterized in mechanistic and kinetic studies.
Molecules
The current study focused on the laboratory approach in conjunction with computational methods for the synthesis and bioactivity assessment of unique 2-tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines (2a–2k). Processes included cyclizing 1-aroyl-3-arylthioureas with propan-2-one in the presence of trimethylamine and bromine. By using spectroscopic techniques and elemental analyses, structures were elucidated. To assess the electronic properties, density functional theory (DFT) calculations were made, while binding interactions of synthesized derivatives were studied by the molecular docking tool. Promising results were found during the evaluation of bioactivity of synthesized compounds against alkaline phosphatase. The drug likeliness score, an indicator used for any chemical entity posing as a drug, was within acceptable limits. The data suggested that most of the derivatives were potent inhibitors of alkaline phosphatase, which in turn may act as lead molecules to synthesize de...