Design and synthesis of aza-flavones as a new class of xanthine oxidase inhibitors

Rajni Dhiman, Sahil Sharma, Gagandip Singh, Kunal Nepali, Preet Mohinder Singh Bedi

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

In an attempt to develop non-purine-based xanthine oxidase (XO) inhibitors, keeping in view the complications reported with the use of purine-based XO inhibitors, the flavone framework (a class possessing XO inhibitory potential) was used as lead structure for further optimization. By means of structure-based classical bioisosterism, quinolone was used as an isoster for chromone (a bicyclic unit present in flavones), owing to the bioactive potential and drug-like properties of quinolones. This type of replacement does not alter the shape and structural features required for XO inhibition, and also provides some additional interaction sites, without the loss of hydrogen bonding and hydrophobic and arene-arene interactions. In the present study, a series of 2-aryl/heteroaryl-4-quinolones (aza analogs of flavones) was rationally designed, synthesized and evaluated for in vitro XO inhibitory activity. Some notions about structure-activity relationships are presented indicating the influence of the nature of the 2-aryl ring on the inhibitory activity. Important interactions of the most active compound 3l (IC50 = 6.24 μM) with the amino acid residues of the active site of XO were figured out by molecular modeling. To develop non-purine-based xanthine oxidase inhibitors, the flavone framework was used as lead structure for further optimization. By means of structure-based classical bioisosterism, quinolone was used as an isoster for chromone. This type of replacement does not alter the shape and structural features required for xanthine oxidase inhibition. The rationally designed and synthesized series of 2-aryl/heteroaryl-4-quinolones (aza analogs of flavones) was evaluated for in vitro xanthine oxidase inhibitory activity.

Original languageEnglish
Pages (from-to)7-16
Number of pages10
JournalArchiv der Pharmazie
Volume346
Issue number1
DOIs
Publication statusPublished - Jan 1 2013
Externally publishedYes

Fingerprint

Flavones
Xanthine Oxidase
flavone
Quinolones
4-Quinolones
Chromones
Hydrogen Bonding
Structure-Activity Relationship
Inhibitory Concentration 50
Catalytic Domain
Amino Acids

Keywords

  • Bioisosterism
  • Flavones
  • Isosteric
  • Quinolones
  • Xanthine oxidase

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery

Cite this

Design and synthesis of aza-flavones as a new class of xanthine oxidase inhibitors. / Dhiman, Rajni; Sharma, Sahil; Singh, Gagandip; Nepali, Kunal; Singh Bedi, Preet Mohinder.

In: Archiv der Pharmazie, Vol. 346, No. 1, 01.01.2013, p. 7-16.

Research output: Contribution to journalArticle

Dhiman, Rajni ; Sharma, Sahil ; Singh, Gagandip ; Nepali, Kunal ; Singh Bedi, Preet Mohinder. / Design and synthesis of aza-flavones as a new class of xanthine oxidase inhibitors. In: Archiv der Pharmazie. 2013 ; Vol. 346, No. 1. pp. 7-16.
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