Incorporation of an Intramolecular Hydrogen-Bonding Motif in the Side Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. falciparum

Madrid, Peter B.; Liou, Ally P.; DeRisi, Joseph L.; Guy, R. Kiplin

doi:10.1021/jm701572a

Cited by 29 publications

(66 citation statements)

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“…Previous data showing that several chloroquine analogs containing an intramolecular hydrogen bonding motif were potent against multidrug-resistant P. falciparum, led Madrida et alto the exploration of the importance of this motif [247]. So, 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability were synthesized, as simple modifications, significantly altering the pKa and sterics of the basic side chain in chloroquine analogs.…”

Section: Intramolecular Hydrogen Bondsmentioning

confidence: 99%

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It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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Section: Intramolecular Hydrogen Bondsmentioning

confidence: 99%

“…[209,217,247,399,400] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity [207,210,401,402].…”

Section: Prediction Of Hydrogen Bonds Formationmentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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“…[1][2][3][4][5] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity. [6][7][8][9] The IMHB as described by Desiraju 10 is an attractive interaction in which an electropositive hydrogen atom intercedes between two electronegative fragments of the same molecule and holds them together.…”

Section: Introductionmentioning

confidence: 99%

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

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This study demonstrates that logP oct-tol (difference between logPoctanol and logPtoluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates.We identified experimental protocols for acquiring reliable logP oct-tol values on a set of compounds representing IMHB motifs most prevalent in Medicinal Chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings.Furthermore, computational logP oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB.The proposed interpretation method based on logP oct-tol data allowed categorization of the compounds into 2 groups -with high propensity to form IMHB and poor propensity or poor relevance of IMHB.The relative 1 H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.4

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“…This screen to identify novel antimalarial chemotypes targeting heme crystallization yielded compounds unlike those described in a notable previous effort, a radioisotope screen conducted at Roche, and unlike those based on modifying the quinoline scaffold (13,14,16,23). Possibly as a result of being able to conduct an HTS on unbiased libraries, the compounds identified in this screen had comparable antimalarial efficacies in both the CQ-sensitive strain 3D7 and the CQ-resistant strain Dd2 of P. falciparum.…”

Section: Discussionmentioning

confidence: 91%

Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors

Rush

Baniecki

Mazitschek

et al. 2009

Antimicrob Agents Chemother

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Malaria infects 500 million people annually, a number that is likely to rise as drug resistance to currently used antimalarials increases. During its intraerythrocytic stage, the causative parasite, Plasmodium falciparum, metabolizes hemoglobin and releases toxic heme, which is neutralized by a parasite-specific crystallization mechanism to form hemozoin. Evidence suggests that chloroquine, the most successful antimalarial agent in history, acts by disrupting the formation of hemozoin. Here we describe the development of a 384-well microtiter plate screen to detect small molecules that can also disrupt heme crystallization. This assay, which is based on a colorimetric assay developed by Ncokazi and Egan (K. K. Ncokazi and T. J. Egan, Anal. Biochem. 338:306-319, 2005), requires no parasites or parasite-derived reagents and no radioactive materials and is suitable for a high-throughput screening platform. The assay's reproducibility and large dynamic range are reflected by a Z factor of 0.74. A pilot screen of 16,000 small molecules belonging to diverse structural classes was conducted. The results of the target-based assay were compared with a whole-parasite viability assay of the same small molecules to identify small molecules active in both assays.

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Incorporation of an Intramolecular Hydrogen-Bonding Motif in the Side Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. falciparum

Abstract: is incorrectly listed as a corresponding author with the asterisk symbol (/) by his name. The symbol next to his name should be an open circle (O) indicating his affiliation with the Department of Pharmaceutics.

Cited by 29 publications

References 0 publications

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors

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