Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors

doi:10.1016/j.bmcl.2006.04.013

Bioorganic & Medicinal Chemistry Letters

Volume 16, Issue 13, 1 July 2006, Pages 3434-3439

https://doi.org/10.1016/j.bmcl.2006.04.013 Get rights and content

Abstract

Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, we have prepared a series of potent keto-1,2,4-oxadiazoles designed to explore the P₂ binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.

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Oxidative cyclization of amidoximes and thiohydroximic acids: A facile and efficient strategy for accessing 3,5-disubstituted 1,2,4-oxadiazoles and 1,4,2-oxathiazoles
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Besides this, they have also been employed as ligands for the transition metal complexes and as G-quadruplex ligands for probing DNA superstructure in antitumor research.10,11 Moreover, these five-membered heterocycles have also been applied as stable ester or amide bioisosteres in peptide mimetics.12 On the other hand, 1,4,2-oxathiazoles are the five-membered heterocycles comprised of three different heteroatoms that are barely reported in the literature.13
Synthesis and biological screening of novel 2-morpholinoquinoline nucleus clubbed with 1,2,4-oxadiazole motifs
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Moreover, 1,2,4-oxadiazole, known as an ester isostere, is present in a variety of biologically active compounds, such as benzodiazepine receptor ligands, muscarinic receptor agonists and 5-HT3 receptor antagonists [18]. 1,2,4-Oxadiazole derivatives possess human tryptase inhibitory activity [19], antitrypanosomal activity [20], genotoxic activity [21], peptide inhibitory activity [22], β-amyloid imaging agents in Alzheimer's disease [23], potential combretastatin A-4 (CA-4) analogs [24], antihyperglycemic activity [25] and oxadiazoles mannich bases show antimyco-bacterial activity [26]. In continuation of our efforts to synthesize some novel heterocyclic motifs with biological interest [27–40], herein we report the design, synthesis, antimicrobial evaluation, cytotoxicity and genotoxicity of quinoline based 1,2,4-oxadiazole scaffold.
Novel series of 2-morpholinoquinoline scaffolds (6a-n), containing the 1,2,4-oxadiazole and moiety, was designed and synthesized in good yield (76–86%). The synthesized compounds were screened for their preliminary in vitro antimicrobial activity against a panel of pathogenic strains of bacteria and fungi. Molecular docking and pharmacokinetic study were carried out for the prepared compounds. The cytotoxicity of the synthesized compounds was tested at different concentrations using bioassay of S. pombe cells at the cellular level. The effect of synthesized compounds on the DNA integrity of S. pombe was observed on agarose gel. Compounds 6d, 6e, 6g, 6h, 6j and 6n exhibited excellent antimicrobial potency as compared to the standard drugs (i.e Ampicillin, Norfloxacin, Chloramphenicol, Ciprofloxacin). Compounds 6d, 6e, 6g, 6k and 6n were found to have significant antifungal activity as compared to griseofulvin. Compounds 6f, 6i, 6k, 6l were found very less cytotoxic, while compounds 6d, 6e, 6g, 6h were found to exhibit maximum toxicity. The rest of the synthesized compounds were found to be moderately toxic.
A novel one-pot synthesis of ferrocenyl-substituted 1,2,4-oxadiazoles
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1,2,4-Oxadiazoles are prominent targets for synthetic chemists primarily because of their diverse and potent biological properties [1]. In fact, 1,2,4-oxadiazoles have been reported to exhibit a wide range of biological properties, including analgesic [2], anti-asthmatic [3], anti-diabetic [4], anthelmintic [5], diuretic [6], anti-inflammatory [7], antimicrobial [8], antiparasitic [9], anti-HIV [10], and antitumor [11] activities. They have also been used frequently as bioisosteres of esters and amides [12], and as dipeptide mimetics [13] in a number of pharmacologically important compounds.
One-pot synthesis of 5-ferrocenyl-1,2,4-oxadiazoles via the reaction between 3-ferrocenylpropynal and amidoximes is described. 3-Ferrocenylpropynal reacts with a variety of amidoximes in the presence of KOH in refluxing dioxane to afford a broad range of 5-ferrocenyl-1,2,4-oxadiazole derivatives. The reaction first produces the corresponding conjugate addition product which, upon cyclization and rearrangement, yields the targeted 1,2,4-oxadiazole. The reaction appears to be general for a diversity of amidoximes and tolerates the presence of aryl groups with electron-withdrawing and electron-donating substituents.
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles
2014, Tetrahedron
A novel synthesis of 1,2,4-oxadiazoles and isoxazoles is described by utilizing the reactions between amidoximes and α,β-alkynic aldehydes and/or ketones. Conjugate addition products, obtained from amidoximes and α,β-alkynic aldehydes and/or ketones, afford 1,2,4-oxadiazoles and isoxazoles when treated with bases and acids, respectively. 1,2,4-Oxadiazoles can also be synthesized directly from amidoximes and α,β-alkynic aldehydes in a one-pot manner under basic conditions. The reactions are general for a variety of starting compounds and tolerate the presence of aryl, heteroaryl and alkyl groups.
Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: Synthesis and pharmacological screening
2013, Bioorganic and Medicinal Chemistry Letters
A novel series of pyrazoline amidoxime (2a–d) and pyrazoly-1,2,4-oxadiazole (3a–p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.
Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?
2012, Bioorganic and Medicinal Chemistry Letters
The tetrameric folding of β-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for β-tryptase.

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Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors

Abstract

Graphical abstract

Pulm. Pharmacol. Ther.

Anaesthesia

Cell. Mol. Life Sci.

Curr. Opin. Allergy Clin. Immunol.

IDrugs

Am. J. Physiol.

Curr. Opin. Investig. Drugs (PharmaPress Ltd.)

Curr. Opin. Drug Discov. Devel.