412018-12-3Relevant academic research and scientific papers
Benzoflavone derivatives as potent antihyperuricemic agents
Singh, Jatinder V.,Mal, Gurbachan,Kaur, Gurleen,Gupta, Manish K.,Singh, Amritpal,Nepali, Kunal,Singh, Harbinder,Sharma, Sahil,Bedi, S. Preet Mohinder
, p. 128 - 147 (2019/01/30)
Two series of benzoflavone derivatives were rationally designed, synthesized and evaluated for their xanthine oxidase (XO) inhibitory potential. Among both series, eight compounds (NF-2, NF-4, NF-9, NF-12, NF-16, NF-25, NF-28, and NF-32) were found to exert significant XO inhibition with IC50 values lower than 10 μM. Enzyme kinetic studies revealed that the most potent benzoflavone derivatives (NF-4 and NF-28) are mixed type inhibitors of the XO enzyme. Molecular modeling studies were also performed to investigate the binding interactions of these molecules (NF-4 and NF-28) with the amino acid residues present in the active site of the enzyme. Docking results confirmed that their favorable binding conformations in the active site of XO can completely block the catalytic activity of the enzyme. Benzoflavone derivatives exhibiting potent XO enzyme inhibition also showed promising results in a hyperuricemic mice model when tested in vivo.
Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies
Singh, Harbinder,Singh, Jatinder Vir,Gupta, Manish K.,Singh, Palwinder,Sharma, Sahil,Nepali, Kunal,Bedi, Preet Mohinder S.
, p. 850 - 854 (2017/02/12)
A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC50value of 0.78?nM against cholesterol esterase. Enzyme kinetic studies carried out for A-12, revealed its mixed-type inhibition approach. Molecular protein–ligand docking studies were also performed to figure out the key binding interactions of A-12 with the amino acid residues of the enzyme's active site. The A-12 fits well at the catalytic site and is stabilized by hydrophobic interactions. It completely blocks the catalytic assembly of CEase and prevents it to participate in ester hydrolysis mechanism. The favorable binding conformation of A-12 suggests its prevailing role as CEase inhibitor.
Synthesis and evaluation of naphthoflavones as a new class of non purine xanthine oxidase inhibitors This Letter is dedicated to Dr. K. L. Dhar on the occasion of his 78th birthday.
Singh, Harbinder,Sharma, Sahil,Ojha, Ritu,Gupta, Manish K.,Nepali, Kunal,Bedi
, p. 4192 - 4197 (2014/09/17)
In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 μM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 μM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies.
Selective benzopyranone and pyrimido[2,1-α]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: Synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro
Griffin, Roger J.,Fontana, Gabriele,Golding, Bernard T.,Guiard, Sophie,Hardcastle, Ian R.,Leahy, Justin J. J.,Martin, Niall,Richardson, Caroline,Rigoreau, Laurent,Stockley, Martin,Smith, Graeme C. M.
, p. 569 - 585 (2007/10/03)
A diverse range of chromen-2-one, chromen-4-one and pyrimidoisoquinolin-4- one derivatives was synthesized and evaluated for inhibitory activity against the DNA repair enzyme DNA-dependent protein kinase (DNA-PK), with a view to elucidating structure-activity relationships for potency and kinase selectivity. DNA-PK inhibitory activity varied widely over the series of compounds evaluated (IC50 values ranged from 0.19 to >10 μM), with excellent activity being observed for the 7,8-benzochromen-4-one and pyrimido[2,1-a] isoquinolin-4-one templates. By contrast, inhibitors based on the benzochromen-2-one (coumarin) or 2-aryl-7,8-benzochromen-4-one (flavone) scaffolds were less potent. Crucially, these studies revealed a very constrained structure-activity relationship at the 2-position of the benzopyranone and pyrimido[2,1-a]-isoquinolin-4-one pharmacophore, with only a 2-morpholino or 2-(2′-methylmorpholino) group being tolerated at this position. More detailed biological studies conducted with the most potent inhibitor NU7163 (48; IC50 = 0.19 μM) demonstrated ATP-competitive DNA-PK inhibition, with a Ki value of 24 nM, and 48 exhibited selectivity for DNA-PK compared with the related enzymes ATM, ATR, mTOR, and PI 3-K (p110alpha). Compound 48 sensitized the HeLa human tumor cell line to the cytotoxic effects of ionizing radiation in vitro, a dose modification factor of 2.3 at 10% survival being observed with an inhibitor concentration of 5 μM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure-activity relationships against DNA-PK.
