Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation

Banerjee, Abhisek; Yadav, Pravin; Bajpai, Malini; Sangana, Ramachandra; Gullapalli, Srinivas; Gudi, Girish; Gharat, Laxmikant A.

doi:10.1016/j.bmcl.2012.03.025

Cited by 20 publications

(5 citation statements)

References 27 publications

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“…It should be noted that so‐called 2‐(aminoarylmethylene)malononitriles ( 4Ar ) have been reported before, however, they are usually generated in multistep reactions from malononitrile and activated aromatics, for example, trimethylorthobenzoate, followed by reactions with ammonia or amines. [ 45 , 46 , 47 , 48 , 49 ]…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that so-called 2-(aminoarylmethylene)malononitriles (4Ar) have been reported before, however, they are usually generated in multistep reactions from malononitrile and activated aromatics, for example, trimethylorthobenzoate, followed by reactions with ammonia or amines. [45][46][47][48][49] Variation of the aromatics. In a series of experiments (Scheme 3) we treated different aromatics (benzene, toluene, o,m,p-xylene, mesitylene, and durene) with 1 a and two equivalents of B(C 6 F 5 ) 3 as Lewis acid, first at slightly elevated temperatures (40-80 °C) and then ambient temperatures or even at 0 °C.…”

Section: Electrophilic Aromatic Substitution (Eas) -Synthesis Of Amin...mentioning

confidence: 99%

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A Lewis Acid Stabilized Ketenimine in an Unusual Variant of the Electrophilic Aromatic Substitution

Surkau

Bläsing

Bresien

et al. 2022

Chemistry A European J

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Electrophilic aromatic substitution (EAS) can provide a straightforward approach to the efficient synthesis of functionalized complex aromatic molecules. In general, Lewis acids serve as a beneficial stimulus for the formation of a Wheland complex, the intermediate in the classical SEAr mechanism of EAS, which is responsible for H/E (E=electrophile) substitution under formal H+ elimination. Herein, we report an unusual variant of EAS, in which a complex molecule such as the tricyanomethane, HC(CN)3, is activated with a strong Lewis acid (B(C6F5)3) to the point where it can finally be used in an EAS. However, the Lewis acid here causes the isomerization of the tricyanomethane to the ketenimine, HN=C=C(CN)2, which in turn directly attacks the aromatic species in the EAS, with simultaneous proton migration of the aromatic proton to the imino group, so that no elimination occurs that is otherwise observed in the SEAr mechanism. By this method, it is possible to build up amino‐malononitrile‐substituted aromatic compounds in one step.

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Section: Resultsmentioning

confidence: 99%

Section: Electrophilic Aromatic Substitution (Eas) -Synthesis Of Amin...mentioning

confidence: 99%

A Lewis Acid Stabilized Ketenimine in an Unusual Variant of the Electrophilic Aromatic Substitution

Surkau

Bläsing

Bresien

et al. 2022

Chemistry A European J

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“…4 However, this does not impede the use of the isothiazole nucleus in the creation of a wide variety of bioactive substances; for example, compounds exhibiting anti-poliovirus activity have been synthesized. 5 Promising compounds for the treatment of Parkinson's disease have also been identified, 6 and recently, derivatives suitable for cancer [7][8][9][10][11][12] and diabetes [13][14][15] therapy have been obtained, as well as microbicides. 16,17 The isothiazole heterocycle in microbicides can protect the molecule from the action of enzymes, 18,19 thereby extending the time of the molecule's action, which in turn makes it possible to administer additional doses of the drug less frequently.…”

Section: Introductionmentioning

confidence: 99%

Isothiazoles in the Design and Synthesis of Biologically Active Substances and Ligands for Metal Complexes

et al. 2019

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The chemistry of isothiazoles is being intensively developed, which is evidenced by the wide range of selective transformations involving the isothiazole heterocycle and the high biological activity of its derivatives that can be used as effective new drugs and plant protection chemicals. Some representatives of isothiazoles have proven to be synergists of bioactive substances, which opens the way to lower the doses of drugs used and is especially important in cancer chemotherapy. In the framework of the present review, the accomplishments in the chemistry of isothiazoles over the past 18 years are examined, whilst current strategies for the synthesis of isothiazole-containing molecules and key directions of studies in this field of heterocyclic chemistry are discussed. Considerable attention is paid to chlorinated isothiazoles and strategies for their use in the synthesis of biologically active substances. In addition, a comprehensive review of existing literature in the field of metal complexes of isothiazoles is given, including the results and prospects for the practical use of isothiazole–metal complexes as catalysts for cross-coupling reactions in aqueous and aqueous–alcoholic media (‘green chemistry’).1 Introduction2 Synthesis by Ring-Forming Reactions2.1 Intramolecular Cyclization2.2 (4+1)-Heterocyclization2.3 (3+2)-Heterocyclization2.4 Syntheses by Ring Transformations3 Isothiazoles by Ring Functionalization Reactions: Nucleophilic Substitution, Cross-Coupling and Side-Chain Functionalization4 Selected Syntheses of Biologically Active Isothiazole Derivatives5 Isothiazoles in the Synthesis of Transition-Metal Complexes and in Metal-Complex Catalysis6 Conclusion

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“…Dihydronaphthyridin-2,8-dione derivatives were reported to show potent and selective inhibition of PDE7 [41]. Isothiazole and isoxazole fused pyrimidines showed some potency as PDE7 inhibitorsas well, [42] Thienopyrimidinones, [43] benzothienothiadiazine, [39] and Thioxoquinazoline derivatives showed potent in vitro inhibition of PDE7A1 [44]. Different series of biphenyl-4-methylsulfanylquinazoline derivatives were reported as PDE7A1 inhibitors [45].…”

Section: Introductionmentioning

confidence: 99%

Ultrasound one pot synthesis of fused quinazolinones and quinazolinediones, screening and molecular docking study as phosphodiesterase 7A inhibitors.

et al. 2019

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P HOSPHODIESTERASE 7A enzyme is one of the most recent targets for designing potent anti-inflammatory agents with minimal side effects. Quinazolinones are unique building blocks of wide biological activities. Different quinazolinones were reported to act as Phosphodiesterase 7A inhibitors anti-inflammatory particularly against chronic inflammation and autoimmune disease. Ultrasound is a green convenient method for synthesis of different heterocyclic ring system that is advantageous in terms of yield and reaction time. Ultrasound was used for one pot synthesis of 3-substituted 6-aryldihydroisoindolo[2,1-a] quinazolin-5,11diones and 3-arylquinazolin-2,4(1H,3H)-diones. Seventeen compounds were synthesized in good yields. The synthesized compounds were inspected for in vitro inhibitory activity against phosphodiesterase7A enzyme. Molecular docking was used to study the mode of interaction of all the synthesized compounds into the enzyme phosphodiesterase 7A binding site. Five compounds showed high inhibitory activity of enzyme Phosphodiesterase 7A at micro-molar level compared to reference drug. The compounds showed good recognition at the enzyme binding site in the molecular docking. There was a good agreement between the molecular docking and the biological screening results.

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Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation

Cited by 20 publications

References 27 publications

A Lewis Acid Stabilized Ketenimine in an Unusual Variant of the Electrophilic Aromatic Substitution

A Lewis Acid Stabilized Ketenimine in an Unusual Variant of the Electrophilic Aromatic Substitution

Isothiazoles in the Design and Synthesis of Biologically Active Substances and Ligands for Metal Complexes

Ultrasound one pot synthesis of fused quinazolinones and quinazolinediones, screening and molecular docking study as phosphodiesterase 7A inhibitors.

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