Synthesis of Berberine—Efflux Pump Inhibitor Hybrid Antibacterials

Bremner, John B.; Kelso, Michael J.

doi:10.1080/00397910903457415

Cited by 12 publications

(10 citation statements)

References 15 publications

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“…Our previously reported synthesis of SS14-P ( 3 ) [12] had involved reacting 8-allyldihydroberberine [13] in the final step with the key benzylic bromide intermediate 16 , which had been prepared via functional-group manipulations with the precursor methyl ester 13 . In the prior work, 13 had been synthesised directly from indole and methyl-4-iodobenzoate in a single step using the rhodium( III )-catalysed indole C2-arylation method reported by Sames et al [14] Although this reaction invariably provided some 13 , the yields were typically low (max.…”

Section: Chemistrymentioning

confidence: 99%

“…The key intermediate 16 was then obtained from 13 using our reported three-step nitration, reduction, bromination sequence. [12] …”

Section: Chemistrymentioning

confidence: 99%

“…[12] Catalytic Finkelstein conversion of bromide 16 in situ to the iodide with 10 mol-% NaI in CH 3 CN at 70°C in the presence of 8-acetonyldihydroberberine 17 provided SS14-P ( 3 ) in 40% yield. Preparative reverse phase (RP)-HPLC purification in the presence of 0.1% HCl initially gave mixed Cl − , Br − and I − salts that were subsequently converted to pure Cl − salts of 3 by anion exchange (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

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On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials

et al. 2014

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Berberine–INF55 hybrids are a promising class of antibacterials that combine berberine and the NorA multidrug resistance pump inhibitor INF55 (5-nitro-2-phenylindole) together in one molecule via a chemically stable linkage. Previous studies demonstrated the potential of these compounds for countering efflux-mediated antibacterial drug resistance but they didn’t establish whether the compounds function as originally intended, i.e. with the berberine moiety providing antibacterial activity and the attached INF55 component independently blocking multidrug resistance pumps, thereby enhancing the activity of berberine by reducing its efflux. We hypothesised that if the proposed mechanism is correct, then hybrids carrying more potent INF55 pump inhibitor structures should show enhanced antibacterial effects relative to those bearing weaker inhibitors. Two INF55 analogues showing graded reductions in NorA inhibitory activity compared with INF55 were identified and their corresponding berberine–INF55 hybrids carrying equivalent INF55 inhibitor structures synthesised. Multiple assays comparing the antibacterial effects of the hybrids and their corresponding berberine–INF55 analogue combinations showed that the three hybrids all show very similar activities, leading us to conclude that the antibacterial mechanism(s) of berberine–INF55 hybrids is different from berberine–INF55 combinations.

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Section: Chemistrymentioning

confidence: 99%

“…The key intermediate 16 was then obtained from 13 using our reported three-step nitration, reduction, bromination sequence. [12] …”

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials

et al. 2014

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“…The synthesis of SS14 has been described previously (2). The synthesis of SS14-M and SS14-P is to be reported elsewhere (7).…”

Section: Methodsmentioning

confidence: 99%

Berberine-INF55 (5-Nitro-2-Phenylindole) Hybrid Antimicrobials: Effects of Varying the Relative Orientation of the Berberine and INF55 Components

Tomkiewicz

Casadei

Larkins-Ford

et al. 2010

Antimicrob Agents Chemother

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Hybrid antimicrobials containing an antibacterial linked to a multidrug resistance (MDR) pump inhibitor make up a promising new class of agents for countering efflux-mediated bacterial drug resistance. This study explores the effects of varying the relative orientation of the antibacterial and efflux pump inhibitor components in three isomeric hybrids (SS14, SS14-M, and SS14-P) which link the antibacterial alkaloid and known substrate for the NorA MDR pump berberine to different positions on INF55 (5-nitro-2-phenylindole), an inhibitor of NorA. The MICs for all three hybrids against wild-type, NorA-knockout, and NorA-overexpressing Staphylococcus aureus cells were found to be similar (9.4 to 40.2 M), indicating that these compounds are not effectively effluxed by NorA. The three hybrids were also found to have similar curing effects in a Caenorhabditis elegans live infection model. Each hybrid was shown to accumulate in S. aureus cells to a greater extent than either berberine or berberine in the presence of INF55, and the uptake kinetics of SS14 were found to differ from those of SS14-M and SS14-P. The effects on the uptake and efflux of the NorA substrate ethidium bromide into S. aureus cells in the presence or absence of the hybrids were used to confirm MDR inhibition by the hybrids. MDR-inhibitory activity was confirmed for SS14-M and SS14-P but not for SS14. Molecular dynamics simulations revealed that SS14 prefers to adopt a conformation that is not prevalent in either SS14-M or SS14-P, which may explain why some properties of SS14 diverge from those of its two isomers. In summary, subtle repositioning of the pump-blocking INF55 moiety in berberine-INF55 hybrids was found to have a minimal effect on their antibacterial activities but to significantly alter their effects on MDR pumps.

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“…The next generation of antibiotics may consist of hybrids containing structures based on fluoroquinolones, anthracyclines, oxazolidines, macrolides and others [187]. The advantages of such systems can produce a covalent binding that can make the Kitson pharmacokinetic characteristics of these molecules more reliable and improve the penetration of each component into the cell [188,189]. Consequently, the drug efficacy will increase due to inhibition of two targets but also the resistance to one or both antibiotics can be circumvented.…”

Section: Hybrid Antibioticsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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Synthesis of Berberine—Efflux Pump Inhibitor Hybrid Antibacterials

Abstract: This paper reports the compact synthesis of two isomeric dual-action hybrid antimicrobials where the 13-position of the antibacterial berberine has been linked via 3'- and 4'-methylene bridges to INF55 (5-nitro-2-phenylindole), an inhibitor of the bacterial NorA multidrug-resistance pump.

Cited by 12 publications

References 15 publications

On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials

On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials

Berberine-INF55 (5-Nitro-2-Phenylindole) Hybrid Antimicrobials: Effects of Varying the Relative Orientation of the Berberine and INF55 Components

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

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