HIV Protease Inhibitory Bis-benzamide Cyclic Ureas:  A Quantitative Structure−Activity Relationship Analysis

Wilkerson, Wendell W.; Akamike, E.; Cheatham, W. W.; Hollis, Andrea; Collins, R. D.; Delucca, I.; Lam, Patrick Y.S.; Ru, Yu

doi:10.1021/jm9602773

Cited by 36 publications

(43 citation statements)

References 22 publications

(54 reference statements)

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“…More noticeable is the negative coef- ficient with Clog P. This suggests that the inhibitory potency decreases linearly with the hydrophobicity. Equation (10) indicates that the inhibitory potency depends on the hydrogen bonding ability of substituents. The correlation matrix between pK i and the descriptors is listed in Table 2.…”

Section: Classical Qsar Studymentioning

confidence: 99%

QSAR Study of Cyclic Urea Type HIV‐1 PR Inhibitors Using Ab Initio MO Calculation of Their Complex Structures with HIV‐1 PR

2008

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A quantitative structure-activity relationship study was carried out on a series of cyclic urea type HIV-1 protease inhibitors. In order to determine the atomic and electronic mechanisms in detail, three-dimensional and electronic descriptors were calculated with the molecular dynamics and ab initio fragment molecular orbital calculation of the whole complex structure of HIV-1 protease with each inhibitor. Two descriptors showing correlation with the inhibitory potency were the total interaction energy and the change in the accessible surface area on complex formation with HIV-1 protease. The major contributions to the total electronic interaction energy were found to be from Asp25/25', Asp30/30' and Ile50/50'. The interaction energy with Asp30/30' was nicely correlated with the total electronic interaction energy and also with the charge transfer from Asp30/30', which is in close contact with the substituted moiety in each inhibitor. As well as the hydrophobic interaction, the charge redistribution among the inhibitor and surrounding residues was suggested to govern the variation in the inhibitory potency. The results obtained in this work can help us to reinterpret the classical QSAR descriptors proposed by Garg et al.

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Section: Classical Qsar Studymentioning

confidence: 99%

QSAR Study of Cyclic Urea Type HIV‐1 PR Inhibitors Using Ab Initio MO Calculation of Their Complex Structures with HIV‐1 PR

2008

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“…After the development of the final model, additional data for 45 compounds were found from the literature [33,34] and it was used for further external validation (see Section 5).…”

Section: Methodsmentioning

confidence: 99%

“…tained from two sources [33,34]. The experimental and predicted activity data, as well as calculated molecular descriptors are available in Supporting Information Table 2.…”

Section: Full Papersmentioning

confidence: 99%

QSAR Modeling of HIV‐1 Protease Inhibition on Six‐ and Seven‐membered Cyclic Ureas

Takkis

Sild

2009

QSAR Comb. Sci.

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A Quantitative Structure -Activity Relationship (QSAR) analysis was carried out on a dataset of 135 six-and seven-membered cyclic urea-based Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitors. Using a larger and more diverse dataset than previous studies reported in literature allowed a more comprehensive analysis. A large set of molecular descriptors, calculated with CODESSA PRO, was used in Multiple Linear Regression (MLR) analysis and the resulting four-parameter model enabled accurate prediction of inhibitory activity for the structures both in training and external validation sets. The squared correlation coefficient for both sets combined is 0.824. Descriptors in the final model characterize the size and shape of the molecule and its charge distribution. Non-linear relationships between the HIV-1 protease inhibition activity and some descriptors are significant and described with simple non-linear transformations. After the model development, another dataset of 45 compounds was collected and additional external validation was performed.

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“…9 Our analogues generally showed greater activity against the family of PDGF receptors and poorer activity against Abl, providing a platform for further drug development against the therapeutically important PDGF receptor family. Recently, we have also prepared a new series of analogues, 10 replacing the NH group of the 2-aminopyrimidine ring (general structure I, compound I, Figure 1) with the alternative binding group NHCO (general structure II, compounds ii-vi, Figure 1), in order to improve their activities against protein kinases. The methodology for the synthesis of N-substituted aminopyrimidines was based on the construction of the heterocycle by condensation of moieties containing the required substituents.…”

Section: Introductionmentioning

confidence: 99%

“…10 Despite the seeming simplicity of that transformation, some problems arised during their synthesis. Surprisingly, direct treatment of 2-aminopyrimidines with substituted benzoyl chlorides, in the presence of triethylamine, resulted in N,N-dibenzoyl derivatives and unreacted amine.…”

Section: Introductionmentioning

confidence: 99%

Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

Théodorou¹,

Gogou²,

Giannousi³

et al. 2013

Arkivoc

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During the N-benzoylation reaction for the synthesis of N-substituted aminopyrimidines, an undesired N,N-diacylation reaction took place. The extension of this N-acylation reaction to a series of several 2-aminopyrimidines, aminopyrazines and highly deactivated anilines produced analogous results. The possible mechanism responsible for that behavior is investigated and an advantageous alternative procedure for the clean formation of the desired amides is suggested.

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HIV Protease Inhibitory Bis-benzamide Cyclic Ureas: A Quantitative Structure−Activity Relationship Analysis

Cited by 36 publications

References 22 publications

QSAR Study of Cyclic Urea Type HIV‐1 PR Inhibitors Using Ab Initio MO Calculation of Their Complex Structures with HIV‐1 PR

QSAR Study of Cyclic Urea Type HIV‐1 PR Inhibitors Using Ab Initio MO Calculation of Their Complex Structures with HIV‐1 PR

QSAR Modeling of HIV‐1 Protease Inhibition on Six‐ and Seven‐membered Cyclic Ureas

Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

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