Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads
Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC50 values of 3.2 and 4.1 μM. Synthetic exploration of hit 59 (IC50 = 4.1 μM) yielded 25 lead inhibitors with the best illustrating IC50 of 3.0 μM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts.
Habash, Maha,Taha, Mutasem O.
experimental part
p. 4746 - 4771
(2011/09/20)
Isopropyl N-arylmalonamates. Synthesis, structure, conformation and reactions with carbon disulfide
Acylation of aromatic amines 1 with diisopropyl malonate (2) leads to a mixture of isopropyl N-arylmalonamates 3 and malonanilides 4. The reaction of 3 with carbon disulfide in the presence of sodium hydride gives disodium salts 5. Treatment of 5 with an alkylating agent yields the open-chain or cyclic ketene dithioacetals 6, 7 or 8. The molecular structure, hydrogen bonding and preferential conformation of the isopropyl N-arylmalonamates 3, 6 and 7 were investigated using correlation analyses of IR, 13C NMR and AMI semiempirical data.
Synthesis of Benzo-halogenated 4-Hydroxy-2(1H)-quinolones
Malondianilides 3 derived from dichloro substituted anilines 2 undergo cyclization to afford 4-hydroxy-2(1H)-quinolones 4 in very good yields using methane sulfonic acid-phosphorus pentoxide as catalyst. 3,4-Dichloro anilines 5 can be shown to yield two i
Kappe, Thomas,Karem, Abdel S.,Stadlbauer, Wolfgang
p. 857 - 862
(2007/10/02)
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