Correction: Development of highly active anti-<i>Pneumocystis</i> bisbenzamidines: insight into the influence of selected substituents on the <i>in vitro</i> activity

Maciejewska, Dorota; Żabiński, Jerzy; Rezler, Mateusz; Kaźmierczak, Paweł; Collins, Margaret S.; Ficker, L.; Cushion, Melanie T.

doi:10.1039/c7md90042b

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“…In continuing the search for new drug candidates, we have taken into account the promising activity and very low cytotoxicity received for 3-phenylsulfonyl-1,5-bis(4-amidino-2,6-dimethylphenoxy)-3-azapentane dihydrochloride. 37 We synthesized three new bis-benzamidines 7–9 in which two sulfanilide groups are in the ortho -, meta - and para -positions of the benzene ring. Moreover, these derivatives represent molecules with less mobile linker connecting bis-benzamidine moieties, which can have an impact on cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features

et al. 2019

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This work presents drug-likeness and the cardiotoxicity profiles of six potent pentamidine analogs 1-6 and three new compounds 7-9 as chemotherapeutics for therapy of Pneumocystis jiroveci pneumonia. A combination of experimental and computational approaches was used in the cardiotoxicity examination. The hERG trafficking and functionality of the hERG currents were tested by western blot analyses, immunofluorescent staining procedures, and patch-clamp electrophysiological assays. Cardiotoxicity combined with blocking the hERG K + channel was predicted, and then simulated by docking to the CSM-TM model 732 protein. Location of pentamidines in the proximity of Leu622, Thr623, Ser649, Tyr652, Ala653, and Phe656, and the high energies of interactions were in accordance with probable blocking of the hERG channel. However, in the biochemical experiments, no significant changes in I hERG densities and a minor effect on hERG maturation were observed. Predicted metabolic transformation of pentamidines with S atoms in the aliphatic linker leads to oxidation of one S atom, but those with the phenyl sulfanilide moiety can be oxidized to chinones. The tested pentamidines characterized by the presence of sulfur atoms or sulfanilide groups, have favorable drug-likeness parameters and are promising lead structures in the development of new potent chemotherapeutics against PJP.All studied pentamidines 1-9 are analyzed in the dicationic form. The predicted drug-likeness parameters (the topological 38360 | RSC Adv., 2019,9,[38355][38356][38357][38358][38359][38360][38361][38362][38363][38364][38365][38366][38367][38368][38369][38370][38371] This journal is View Article Online were predicted to be above 4 indicating a higher risk for hERG K + channel inhibition. 68 We also examined logarithm of the distribution coefficient values (log D) at pH 7.4, which give an estimate of the lipophilicity of a drug at the pH of blood plasma. The average values of log D are within the range À0.03 to 2.75 and not exceeding the traditionally cutoff value of 3.5. Fig. 3 Products of metabolism of pentamidine and 1-9 derivatives.This journal is

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Section: Introductionmentioning

confidence: 99%

Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features

et al. 2019

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“…Level of LDH, SGOT, and SGPT are elevated only for 1 and 4 indicating some hepatic problems. The cytotoxicity of 1-6 were tested experimentally in our former works [35][36][37] with other groups of pentamidines, which can explain observed data. In these assays, the majority of compounds were not cytotoxic (also those with the sulfobenzene group), only compounds 1 and 4 exhibited less or moderate cytotoxicity.…”

Section: Assessing Of Drug-likeness Parametersmentioning

confidence: 99%

“…Keppen-Lubinsky syndrome is an extremely rare condition associated with KIR3.2 gain-of-function mutations. Its phenotype encompasses lipodystrophy, hypertonia, hyperreflexia, developmental delay and intellectual disability [37,38]. Familial hyperaldosteronism type III is associated with loss-offunction mutations in KIR3.4 channel proteins.…”

Section: Diseases and Syndromes Associated With Kir Channel Dysfunctionmentioning

confidence: 99%

“…[32][33][34] In an effort to find a more efficient therapeutic agent for the treatment of PJP, our laboratory has developed a number of linear pentamidine analogs which showed excellent anti-Pneumocystis activity. [35][36][37] Among them, we have designed, synthesized and evaluated six bisbenzamidines 1-6 characterized by the presence of a one or two sulfur atoms in the linker and introduction of alkyl substituents to the amidine groups (see Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…In continuing the search for new drug candidates, we have taken into account the promising activity and very low cytotoxicity received for 3-phenylsulfonyl-1,5-bis(4-amidino-2,6-dimethylphenoxy)-3-azapentane dihydrochloride. 37 We synthesized three new bis-benzamidines 7-9 in which two sulfanilide groups are in the ortho-, meta-and para-positions of the benzene ring. Moreover, these derivatives represent molecules with less mobile linker connecting bisbenzamidine moieties, what can have an impact on cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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determines cardiac systolic/diastolic function, and abnormalities could result in cardiac arrhythmia and even sudden cardiac death (Hoffman and Cranefield, 1960).Chapter 1 2. Phase 1 is a phase of rapid repolarization beginning with rapid inactivation of voltage-gated Na + channels that aborts inward INa. At the same time, a transient outward K + current, Ito (Rudy, 2008), by activating voltage-gated K + channels briefly, leads to a slight negative shift of membrane potential (Santana et al., 2010; Grant, 2009). 3. Phase 2 is the plateau phase. The slow delayed rectifier K + current, IKs is slowly activated allowing K + efflux, which is partially balanced by the inward ICa,L activated at phase 0. Moreover, the increased concentration of intracellular Ca 2+ also activates Ca 2+ channels on the sarcoplasmic reticulum (SR), the so-called Ryanodine receptors, allowing Ca 2+ efflux move from SR to cytoplasm, a Ca 2+ activated Clcurrent (Hoffman, 1960) allowing Cl − into the cell, and ionic pumps like Na + -Ca 2+ exchanger and Na + -K + pump. All these ionic movements result in the membrane potential remaining almost constant with a low level of membrane repolarizing (Grant, 2009; Grunnet, 2010). 4. Phase 3 is the phase of rapid repolarization because L-type Ca 2+ channels close, while IKs remains activated and the negative change in membrane potential induces more K + currents, primarily the rapid delayed rectifier K + current (IKr) and the inward rectifier K + current (IK1). The strong outward K + current brings the membrane potential back to its resting value. The voltage-gated delayed rectifier K + channels close at ~-85 mV, while IK1 remains active and helps to maintain the resting membrane potential (Grant, 2009; Kubo et al., 2005). 5. Phase 4 represents the resting phase. The resting membrane potential is stable and more or less constant at ~-80 mV, resulting from perfect balance between influx of ions (e.g. Na + and Ca 2+ ) and efflux of ions (e.g. K + , Cland HCO3 -) (Santana, 2010; Morad and Tung, 1982). Among these ion channels, the potassium channel family is the largest branch. It can be broadly divided into two subfamilies by its transmembrane structure features: the six-transmembrane-helix voltage-gated potassium channel (Kv) and the two-transmembrane-helix inward rectifier potassium channel (KIR) (Ho et al., 1993).

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Correction: Development of highly active anti-Pneumocystis bisbenzamidines: insight into the influence of selected substituents on the in vitro activity

Abstract: Correction for ‘Development of highly active anti-Pneumocystis bisbenzamidines: insight into the influence of selected substituents on the in vitro activity’ by D. Maciejewska et al., Med. Chem. Commun., 2017, 8, 2003–2011.

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Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features

Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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Correction: Development of highly active anti-Pneumocystis bisbenzamidines: insight into the influence of selected substituents on the in vitro activity

Abstract: Correction for ‘Development of highly active anti-Pneumocystis bisbenzamidines: insight into the influence of selected substituents on the in vitro activity’ by D. Maciejewska et al., Med. Chem. Commun., 2017, 8, 2003–2011.

Cited by 2 publications

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Drug-likeness of linear pentamidine analogues and their impact on the hERG K+channel – correlation with structural features

Drug-likeness of linear pentamidine analogues and their impact on the hERG K+channel – correlation with structural features

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features

Drug-likeness of linear pentamidine analogues and their impact on the hERG K⁺channel – correlation with structural features