In vitro screening of pentamidine analogs against bacterial and fungal strains

Maciejewska, Dorota; Żabiński, Jerzy; Kaźmierczak, Paweł; Wójciuk, Karolina; Kruszewski, Marcin; Kruszewska, Hanna

doi:10.1016/j.bmcl.2014.04.075

Cited by 12 publications

(10 citation statements)

References 31 publications

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“… 11 − 13 Apart from its antiprotozoal activity, pentamidine is also known to have moderate antibacterial activity against Gram-positive species. 14 , 15 Furthermore, pentamidine has also been shown to have anti-cancer activity by restoring the tumor-suppressing activity of p53, is capable to bind A/T-rich regions of double-stranded DNA, and can non-specifically bind and disrupt tRNA secondary structures. 16 − 19 Unsurprisingly, this broadly active compound has a high incidence of side effects such as nephrotoxicity, hypotension, hypoglycaemia, or local reactions to the injection.…”

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confidence: 99%

Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

et al. 2021

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Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure–activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii , Klebsiella pneumoniae , Pseudomonas aeruginosa, and Escherichia coli , including polymyxin- and carbapenem-resistant strains.

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confidence: 99%

Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

et al. 2021

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“…It is known that 2‐substituted 2‐imidazolines are potent antimicrobials . In the case of thiepine 21 , a lower antifungal activity was observed in comparison with 9 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

et al. 2016

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A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine (16) efficiently killed Candida albicans at 15.6 μg/mL and showed no embryotoxicity at 75 μg/mL. Derivative 8-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl][1]benzothiepino[3,2-c]pyridine (23) caused significant hemolysis and in vitro DNA interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.

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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%

“…On the other hand, KIR2.1 gain-offunction mutations result in cardiac phenotypes, atrial fibrillation and short QT syndrome, explained by increased repolarization capacity and thus shortened cardiac action potentials [34,35]. Thyrotoxic hypokalemic periodic paralysis associated with KIR2.6 loss-of-function mutations affect skeletal muscle excitability under thyrotoxic conditions [36]. Keppen-Lubinsky syndrome is an extremely rare condition associated with KIR3.2 gain-of-function mutations.…”

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%

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Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

Qile¹

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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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In vitro screening of pentamidine analogs against bacterial and fungal strains

Cited by 12 publications

References 31 publications

Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

Structure–Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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