Naslov
Lipophilicity of novel biscoumarin - HIV-1 integrase inhibitor

Autori
Mornar, Ana ; Medić-Šarić, Marica ; Jasprica, Ivona ; Tunjić, Iva

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
The 3rd Lipophilicity Symposium - Physochemicaland Biological Profiling in Drug Research (LogP2004 ) : abstracts / Folkers, Gerd - Zürich : ETH, 2004, A-13

Skup
Lipophilicity Symposium (3 ; 2004)

Mjesto i datum
Zürich, Švicarska, 29.02.2004. - 04.03.2004

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
lipophilicity; biscoumarin; HIV-1 integrase

Sažetak
Human immunodeficiency virus type 1 (HIV-1) is the agent of the acquired immunodeficiency sydrom (AIDS). HIV-1 integrase is an enzyme that mediates the integration of HIV-1 DNA into a host chromosome and is essential to replication of the virus. HIV-1 integrase is an attractive target for therapeutic development against AIDS since there are no known cellular enzymes that function similary, raising the hope that integrase inhibitors could be relatively non-toxic. Recent reports have appeared on high HIV-1 integrase inhibitory potency of certain biscoumarin analogues. In the previous studies it was shown that the active pharmacophore consisted of a coumarin dimer containing an aryl substituent on the central linker methylene. QSAR studies demostrated that the aromatic hydroxyl group and lipophilicity of the aryl substituent on the central linker methylene were associated with bioactivity of HIV-1 integrase inhibitors. The aim of our work was to prepare 3, 3'-(4-hydroxybenzylidene)bis[4-hydroxycoumarin] and investigate its lipophilicity using potentiometric titration method and theoretical approaches. The potentiometric titration method was chosen as the easiest method of log P measurment, and provides detailed information on the partitioning characteristics of target compound at all pH values. pKa, log P and log D values were determinated using Sirius instrument GLpKa. Experimentally determinated log P value (3.180) was correlated with log P values predicted by different computer programs: Hyperchem 7.0 (2.508), XLOGP 2.0 (4.22), KowWin (3.0772), MLOGP (2.519), CLOGP (4.129), milogP (4.188), ALOGPS 2.1 (3.1), IA logP (3.93) Vega-Crippen (5.0823) and Vega-Broto (6.847). The best correlation between experimentally determinated and calculated values was found for the KowWin and ALOGPS 2.1 programs. The correlation between experimental and calculated values was consider in order to evaluate the predictive power of the approaches applied to compute the lipophilicity of biscoumarins. The e-state indices encode relevant information and their implementation in powerful statistical tools as the neural networks seems to offer a promising alternative for more consistent log P value.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

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