Quantitative Structure-Activity Relationship Studies of a Series of Sulfa Drugs as Inhibitors of
            <i>Pneumocystis carinii</i>
            Dihydropteroate Synthetase

Johnson, Theresa; Khan, Ikhlas A.; Avery, Mitchell A.; Grant, Juliana; Meshnick, Steven R.

doi:10.1128/aac.42.6.1454

Cited by 13 publications

(4 citation statements)

References 11 publications

(19 reference statements)

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“…From the given structure of drug molecules (see insets in Figures and S1), one could intuitively expect a high lipophilicity because of the presence of aromatic ring with delocalized π-electrons. These drugs, however, have isolated negative charges on the carboxylate or amide group once deprotonated, which are unshielded in their molecular structures as well. − Such localized negative charges could dominate the effective hydrophilicity of the drug ions, especially when they transfer across a water/DCE interface. In fact, nanopipet voltammetry in this study revealed an extremely high value of effective hydrophilicity for deprotonated quinolone and sulfonamide ions.…”

Section: Resultsmentioning

confidence: 99%

Kinetics of Antimicrobial Drug Ion Transfer at a Water/Oil Interface Studied by Nanopipet Voltammetry

Puri

Kim

2019

Anal. Chem.

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Effective delivery and accumulation of antimicrobial agents into the microbial organism is essential for the treatment of bacterial infections. Transports of hydrophilic drug molecules, however, encounter a robust barrier of hydrophobic double membrane cell envelope, thus, leading to drug-resistance in Gram-negative bacteria. Accordingly, a deeper understanding about a transit of charged molecules through a bacterial membrane is needed to remediate the antibacterial resistance. Herein, we apply a steady-state voltammetry using nanopipet-supported interfaces between two immiscible electrolyte solutions (ITIES) to quantitatively study transport-kinetics of antimicrobial drug ions (quinolones and sulfonamides) at a water/oil interface. Importantly, ITIES can mimic a cellular membrane system, thus, being employed as insightful surrogates for the kinetic study of drug entry through bacterial cytoplasmic membranes. This approach enables us to voltammetrically and amperometrically detect redox-inactive drug ions as pristine under physiological conditions. Considerably slow kinetics of drug-ion transports are successfully measured by nanopipet voltammetry and theoretically analyzed. This analysis reveals that the drug-ion transport is ∼3 orders of magnitude slower than tetrabutylammonium ion transport. In addition, the extreme hydrophilicity of drug ions in comparison to ClO4 – is quantitatively assessed from half-wave potentials of obtained voltammograms. The high hydrophilicity exclusively attributed to localized negative charges on carboxylate or amide group of deprotonated quinolone or sulfonamide, respectively, may play a dominant role in sluggish kinetics due to the increase in energy barriers upon interfacial ion transfer. Notably, this study using nanopipet voltammetry provides physicochemical insights on the correlation between structural properties of pristine drug ions and their transfer kinetics at a water/oil interface in lieu of biological membranes.

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Section: Resultsmentioning

confidence: 99%

Kinetics of Antimicrobial Drug Ion Transfer at a Water/Oil Interface Studied by Nanopipet Voltammetry

Puri

Kim

2019

Anal. Chem.

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“…Despite the availability of various anti- Pneumocystis agents including trimethoprim-sulfamethoxazole, pentamidine, clindamycin-primaquine, and atovaquone, recent concerns support the need to develop additional agents [75–77]. While these agents are effective in reducing pathogen burden, drug-related toxicities limit use in some patients.…”

Section: Discussionmentioning

confidence: 99%

Chitinases in Pneumocystis carinii pneumonia

Villegas

Kottom

Limper

2012

Med Microbiol Immunol

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Pneumocystis pneumonia remains an important complication of immune suppression. The cell wall of Pneumocystis has been demonstrated to potently stimulate host inflammatory responses, with most studies focusing on β-glucan components of the Pneumocystis cell wall. In the current study, we have elaborated the potential role of chitins and chitinases in Pneumocystis pneumonia. We demonstrated differential host mammalian chitinase expression during Pneumocystis pneumonia. We further characterized a chitin synthase gene in Pneumocystis carinii termed Pcchs5, a gene with considerable homolog to the fungal chitin biosynthesis protein Chs5. We also observed the impact of chitinase digestion on Pneumocystis-induced host inflammatory responses by measuring TNFα release and mammalian chitinase expression by cultured lung epithelial and macrophage cells stimulated with Pneumocystis cell wall isolates in the presence and absence of exogenous chitinase digestion. These findings provide evidence supporting a chitin biosynthetic pathway in Pneumocystis organisms and that chitinases modulate inflammatory responses in lung cells. We further demonstrate lung expression of chitinase molecules during Pneumocystis pneumonia.

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“…Rather than computing ligand−receptor binding energies (a nontrivial task for metal-binding enzymes such as MMPs), these methods sample steric and electrostatic fields (CoMFA) or calculate similarity indices (CoMSIA) surrounding an established compound set and then correlate differences in those fields or indices with experimental biological activity. Both CoMFA and CoMSIA have been shown in multiple studies − to be powerful and effective techniques for designing novel ligands, improving the potency of existing inhibitors, mapping previously unmodeled active-site properties, and clarifying mechanisms of action.…”

Section: Methodsmentioning

confidence: 99%

A Preliminary in Silico Lead Series of 2-Phthalimidinoglutaric Acid Analogues Designed as MMP-3 Inhibitors

Amin

Welsh

2006

J. Chem. Inf. Model.

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Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.

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Quantitative Structure-Activity Relationship Studies of a Series of Sulfa Drugs as Inhibitors of Pneumocystis carinii Dihydropteroate Synthetase

Cited by 13 publications

References 11 publications

Kinetics of Antimicrobial Drug Ion Transfer at a Water/Oil Interface Studied by Nanopipet Voltammetry

Kinetics of Antimicrobial Drug Ion Transfer at a Water/Oil Interface Studied by Nanopipet Voltammetry

Chitinases in Pneumocystis carinii pneumonia

A Preliminary in Silico Lead Series of 2-Phthalimidinoglutaric Acid Analogues Designed as MMP-3 Inhibitors

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