Synthesis and analgesic-antiinflammatory activity of some 4- and 5-substituted heteroarylsalicylic acids

Jones, Howard; Mw, Fordice; Rb, Greenwald; Hannah, John; Jacobs, Alice K.; Wv, Ruyle; Gl, Walford; Ty, Shen

doi:10.1021/jm00209a002

Cited by 32 publications

(11 citation statements)

References 8 publications

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“…Unfortunately, it did not decrease oxalate excretion in PH1 hepatocytes (Table ). The same isosteric change in the nonformylated furan 27 (C5 isomer) raised thiophene 38 (Figure ), which showed a huge decrease of efficacy (0.82 ± 0.01 vs 0 relative oxalate) while conserving the same potency as mGOi (IC 50 = 39.5 ± 1.1 μM) (Table ). As we did with the furan derivatives, we checked the importance of the orientation of the thiophene by binding it to the polar head by its C3′ carbon atom (compounds 39 and 40 , Figure ).…”

Section: Results and Discussionmentioning

confidence: 99%

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

et al. 2018

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Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.

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Section: Results and Discussionmentioning

confidence: 99%

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

et al. 2018

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“…Other attempts were also made by using different oxidizing agents including the activated carbon-O 2 system9 and palladium-carbon system,10 but neither of these methods gave a satisfactory yield (<2%). In our efforts to find an alternative way to construct the imidazole ring, we tried starting with iminoether11 but abandoned this approach because of the multistep synthesis. Finally, a simple, one-step synthesis of the key intermediate ( 2a-k ) was found (Scheme 2) by reacting the appropriate benzaldehyde ( 1a-h) in ethanol with oxalaldehyde and ammonia hydroxide to construct the imidazole ring system ( 2a-k ) 12.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Novel 2-Aryl-4-benzoyl-imidazoles Targeting the Colchicines Binding Site in Tubulin As Potential Anticancer Agents

et al. 2010

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A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC 50 of the most active compound (5da) was 15.7 nM. ABI analogs have substantially improved aqueous solubility (48.9 μg/mL for 5ga vs. 0.909 μg/mL for SMART-1, 0.137 μg/mL for paclitaxel, and 1.04 μg/mL for Combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogs is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors.

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“…42 • 43 Diflunisal displaced warfarin from its binding sites in humans when the two drugs were given together, 44 although this interaction was not predicted in vitro (Tocco D, unpublished data on file at Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania, 1978). In rats, 14 C diflunisal was distributed into most tissues 34 with relative distribution probably reflecting the blood content of tissues and the drug's route of excretion. Diflunisal entered erythrocytes poorly, and concentrations in the brain were low.…”

Section: Absorption Distribution Metabolism Excretion and Pharmacmentioning

confidence: 99%

Review of the Animal and Clinical Pharmacology of Diflunisal

Davies

1983

Pharmacotherapy

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Diflunisal is a new salicylic acid derivative identified after a search for a compound with improved potency, enhanced gastrointestinal tolerance relative to its antiinflammatory activity, and a longer duration of action than that of aspirin. Animal and clinical studies have confirmed these properties. As an inhibitor of cyclooxygenase tested in vitro in a sheep seminal vesicle preparation, diflunisal was less potent than indomethacin but 10 to 20 times more active than aspirin. In addition, it was shown biochemically to act as a moderate free radical scavenger. Diflunisal is well absorbed from the gastrointestinal tract, is subject to dose-dependent pharmacokinetics (like aspirin), and reaches steady-state levels in a predictable fashion in most persons. The drug is excreted by the kidneys, and its apparent half-life is lengthened in the presence of renal failure. A number of drug interactions have been described. Diflunisal produces reversible effects on platelet aggregation when given in high doses, whereas aspirin produces irreversible aggregation at low doses. Measurements of fecal blood loss and endoscopic examinations have confirmed the improved gastrointestinal tolerance of diflunisal compared to aspirin.

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Synthesis and analgesic-antiinflammatory activity of some 4- and 5-substituted heteroarylsalicylic acids

Cited by 32 publications

References 8 publications

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

Discovery of Novel 2-Aryl-4-benzoyl-imidazoles Targeting the Colchicines Binding Site in Tubulin As Potential Anticancer Agents

Review of the Animal and Clinical Pharmacology of Diflunisal

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