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Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.

ABSTRACT: While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile.

SUBMITTER: Okello M

PROVIDER: S-EPMC3701953 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.

Okello Maurice M Mishra Sanjay S Nishonov Malik M Nair Vasu V

Bioorganic & medicinal chemistry letters 20130523 14

While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained throug ...[more]

PMID: 23746474

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Project description:Objective:The geometric configuration of the intraventricular tunnel is related to the re-intervention of left ventricular outflow tract stenosis after double outlet right ventricle (DORV) correction. Hemodynamic simulation was performed in order to study the influence of the geometric configuration of the IVT on the pressure difference. Methods:CT images of DORV were processed to reconstruct 3D models of left and right ventricular flow chambers and aortic valve orifice, and then the size and relative position of the aortic valve orifice and ventricular septal defect were determined. Twenty five groups of the idealized models were established according to orthogonal test design and computational fluid dynamics method was applied to simulate hemodynamics. Three factors of geometric configuration were considered for the study of their influences on the pressure difference. The first factor is the distance between the ventricular septal defect and the plane of the aortic valve (DSA), the second factor is the ejection angle of blood from left ventricle flowing into the IVT (ALT), and the third factor is the turning radius of the IVT (RTT). SPSS software was employed to perform the orthogonal analysis. Additionally, twelve models with different turning radii were established for hemodynamic analysis, with the turning radii increasing from 0 mm with an interval of 1 mm, so as to study the influence of turning radius on pressure difference of IVT. Results:The analysis of variance showed that only the change of RTT had a significant effect on the pressure difference (P = 0 < 0.05), while the change of DSA and ALT had no significant effect on the pressure difference (P = 0.459 > 0.05, P = 0.263 > 0.05). The pressure difference decreases with the increase of RTT. When RTT reaches 6 mm, the pressure difference gradually remains unchanged with the increase of RTT, and the rate of change is less than 5%. Conclusion:RTT in the IVT is the main factor affecting the pressure difference. A small RTT will lead to a large pressure difference in the IVT. When RTT increases to 6 mm, the pressure difference in the IVT remains nearly unchanged. When performing the right ventricular double outlet correction; the turning radius of the IVT should be about 6 mm to ensure relatively small pressure difference.

Dataset Information

Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.

Publications

Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.

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