TY - JOUR
T1 - Design and synthesis of aza-flavones as a new class of xanthine oxidase inhibitors
AU - Dhiman, Rajni
AU - Sharma, Sahil
AU - Singh, Gagandip
AU - Nepali, Kunal
AU - Singh Bedi, Preet Mohinder
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Bioisosterism
KW - Flavones
KW - Isosteric
KW - Quinolones
KW - Xanthine oxidase
UR - http://www.scopus.com/inward/record.url?scp=84872235042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872235042&partnerID=8YFLogxK
U2 - 10.1002/ardp.201200296
DO - 10.1002/ardp.201200296
M3 - Article
C2 - 23076715
AN - SCOPUS:84872235042
SN - 0365-6233
VL - 346
SP - 7
EP - 16
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 1
ER -