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Papers by Paul Keller
Antibiotics, 2021
Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producin... more Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producing bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are inadequate, expensive, and limited, and thus inexpensive drug treatments for C. difficile infection (CDI) with improved efficacy and specificity are urgently needed. To improve the solubility of our cationic amphiphilic 1,1′-binaphthylpeptidomimetics developed earlier that showed promise in an in vivo murine CDI model we have synthesized related compounds with an N-arytriazole or N-naphthyltriazole moiety instead of the 1,1′-biphenyl or 1,1′-binaphthyl moiety. This modification was made to increase the polarity and thus water solubility of the overall peptidomimetics, while maintaining the aromatic character. The dicationic N-naphthyltriazole derivative 40 was identified as a C. difficile-selective antibacterial with MIC values of 8 µg/mL against C. difficile strains ATC...
Chemistry – A European Journal, 2020
Supporting information for this article is given via a link at the end of the document.
RSC Advances, 2020
Convergent and convenient regioselective synthesis of novel thiazolo[2,3-a]pyrimidines was accomp... more Convergent and convenient regioselective synthesis of novel thiazolo[2,3-a]pyrimidines was accomplished using the one-pot reaction of 6-ethylthiouracil, bromoacetic acid, anhydrous sodium acetate, acetic anhydride, acetic acid and suitable aldehyde.
Organic & Biomolecular Chemistry, 2018
Cascade reactions of indigo with strained electrophiles affords access to previously unknown oxaz... more Cascade reactions of indigo with strained electrophiles affords access to previously unknown oxazocino, pyrazino, and diazepino diindoles with selective anti-plasmodial activity.
The Journal of Organic Chemistry, 2019
The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust na... more The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven diversely functionalized [1H,3′H]-3-substituted 2,2′-diindol-3′-ones were synthesized by this methodology, with several showing submicromolar inhibition and exquisite selectivity against P. falciparum parasites (3D7 and Dd2 strains) in vitro. This work demonstrates the utility of indigo dye as a highly versatile scaffold for the synthesis of structurally diverse, bioactive heterocycles.
Org. Biomol. Chem., 2016
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide H... more From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide HIV-1 integrase (IN) inhibitor was identified. Subsequent optimisation afforded an analogue exhibiting an IC50 value of 2.5 μM.
Organic & biomolecular chemistry, Jan 9, 2015
Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thi... more Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thirty five novel leucine-containing intermediate oxazoles and thiazoles were prepared in this study. This includes the first examples of the direct C-5 arylation of an amino acid dipeptide-derived oxazole. Moderate to excellent antibacterial activity was observed for all new compounds across Gram positive isolates with MICs ranging from 1-16 μg mL(-1). Results for Gram negative E. coli and A. baumannii were more variable, but MICs as low as 4 μg mL(-1) were returned for two examples. Significantly, the in vitro results with a fluoromethyl-oxazole derivative collectively represent the best obtained to date for a member of our binaphthyl peptide antimicrobials.
Tetrahedron, 2015
The allylation of indirubin produced the expected indolic N′-allylindirubin and N,N′-diallylindir... more The allylation of indirubin produced the expected indolic N′-allylindirubin and N,N′-diallylindirubin derivatives in moderate yields, together with the corresponding N-substituted isatin products. At higher temperatures, the base-initiated reaction with allylic halides yielded spiroindolinepyrido[1,2-a]indolediones in a one-pot cascade reaction sequence with yields of up to 70%. These readily accessed, new spiro compounds represent the first reported examples of indirubin participating in cascade reactions. Preliminary in vitro biological testing of some of the products indicated promising activity against some cancer cell lines and against Plasmodium falciparum for two spiro derivatives. Computational methods were used to gain a greater understanding of the UV/Vis spectroscopic data for the N′-substituted and N,N′-disubstituted indirubin derivatives.
Journal of Organometallic Chemistry, 2015
Arsenous chloride-free synthesis of cyclic tertiary organoarsines from arylarsine oxides and di-G... more Arsenous chloride-free synthesis of cyclic tertiary organoarsines from arylarsine oxides and di-Grignard reagents
Beilstein Journal of Organic Chemistry, 2015
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedd... more Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
Organic & Biomolecular Chemistry, 2015
Designed binaphthyl-based, cationic peptidomimetic antimicrobials targetingC. difficile, incorpor... more Designed binaphthyl-based, cationic peptidomimetic antimicrobials targetingC. difficile, incorporating a click-derived 1,2,3-triazole ester isostere at the C-terminus MICs of 4 μg mL−1against three human isolates ofC. difficile.
Tetrahedron, 2006
Synthesis of some cyclic indolic peptoids as potential antibacterials Synthesis of some cyclic in... more Synthesis of some cyclic indolic peptoids as potential antibacterials Synthesis of some cyclic indolic peptoids as potential antibacterials
Tetrahedron, 2008
As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold... more As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 µg/mL.
Organic Letters, 2008
Reagents and solvents were purchased reagent-grade and used without further purification. Toluene... more Reagents and solvents were purchased reagent-grade and used without further purification. Toluene and THF were distilled from sodium benzophenone ketyl. CH 2 Cl 2 was stored over CaCl 2 and distilled from CaH 2. [60]Fullerene was purchased from MER Corporation Tucson, Arizona AZ 85706 USA. All reactions were performed in standard glassware under an inert atmosphere of nitrogen. Flash column chromatography was performed using silica 60 (230-400 mesh, 0.040-0.063 mm) purchased from Merck. ESI SI-2 MS were recorded on a ThermoFinnigan LTQ (Waltham, MA) fitted with a conventional IonMax electrospray ionization source. Spectra were obtained by infusion of a standard solution (2:1 chloroform : methanol). Typical settings were spray voltages between 4-6 kV, capillary temperature 270 o C and sheath gas flow rates at 10 (arbitrary units). 1 H NMR spectra were acquired on a Varian Unity 300 or 500 spectrometer at 300.1 and 499.9 MHz respectively, or a Bruker DMX-600 spectrometer at 600.2 MHz. 13 C NMR spectra were acquired on Varian Unity 300 or 500 spectrometer at 75.4 and 125.0 MHz respectively, or a Bruker DMX-600 spectrometer at 150.9 MHz. Deuterated solvents were obtained commercially (Sigma-Aldrich or Cambridge) and were greater than 99.5 atom % d. All chemical shifts are reported relative to TMS (0.00).
The Journal of Organic Chemistry, 2013
The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot ... more The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a′]diindole, pyrido[1,2-a:3,4-b′]diindole and benzo[b]indolo[1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring Bhomologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through singlecrystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means.
European Journal of Medicinal Chemistry, 2011
The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C2s... more The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C2symmetric binaphthyl scaffold which holds two identical chains consisting of a short linker, a basic amino acid and a small hydrophobic side chain. Antibacterial activity is revealed for a number of derivatives down to an MIC of 2 µg/mL (2 µM) against Staphylococcus aureus-comparable to vancomycin, and an MIC of 31 µg/mL (31 µM) against some vancomycin resistant enterococcal strains.
European Journal of Medicinal Chemistry, 2009
An efficient synthesis of two new N-acetyl-4'-arylphenylalanines is described together with their... more An efficient synthesis of two new N-acetyl-4'-arylphenylalanines is described together with their incorporation in to a number of cationic peptoid antibacterial agents, one of which had an MIC of 7.8 μg/ mL against Staphylococcus aureus.
Chemical Communications, 2010
The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bio... more The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bioxirane, or three steps from 2,2'-biaziridine, both with exceptional enantiopurity
Chemical Communications, 2010
Table 1. Investigation into the Pd(II)-catalysed C-H activation of enamine 10, affording 2,3-disu... more Table 1. Investigation into the Pd(II)-catalysed C-H activation of enamine 10, affording 2,3-disubstituted indole 11.
Beilstein Journal of Organic Chemistry, 2012
The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobi... more The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2–4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.
Antibiotics, 2021
Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producin... more Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producing bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are inadequate, expensive, and limited, and thus inexpensive drug treatments for C. difficile infection (CDI) with improved efficacy and specificity are urgently needed. To improve the solubility of our cationic amphiphilic 1,1′-binaphthylpeptidomimetics developed earlier that showed promise in an in vivo murine CDI model we have synthesized related compounds with an N-arytriazole or N-naphthyltriazole moiety instead of the 1,1′-biphenyl or 1,1′-binaphthyl moiety. This modification was made to increase the polarity and thus water solubility of the overall peptidomimetics, while maintaining the aromatic character. The dicationic N-naphthyltriazole derivative 40 was identified as a C. difficile-selective antibacterial with MIC values of 8 µg/mL against C. difficile strains ATC...
Chemistry – A European Journal, 2020
Supporting information for this article is given via a link at the end of the document.
RSC Advances, 2020
Convergent and convenient regioselective synthesis of novel thiazolo[2,3-a]pyrimidines was accomp... more Convergent and convenient regioselective synthesis of novel thiazolo[2,3-a]pyrimidines was accomplished using the one-pot reaction of 6-ethylthiouracil, bromoacetic acid, anhydrous sodium acetate, acetic anhydride, acetic acid and suitable aldehyde.
Organic & Biomolecular Chemistry, 2018
Cascade reactions of indigo with strained electrophiles affords access to previously unknown oxaz... more Cascade reactions of indigo with strained electrophiles affords access to previously unknown oxazocino, pyrazino, and diazepino diindoles with selective anti-plasmodial activity.
The Journal of Organic Chemistry, 2019
The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust na... more The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven diversely functionalized [1H,3′H]-3-substituted 2,2′-diindol-3′-ones were synthesized by this methodology, with several showing submicromolar inhibition and exquisite selectivity against P. falciparum parasites (3D7 and Dd2 strains) in vitro. This work demonstrates the utility of indigo dye as a highly versatile scaffold for the synthesis of structurally diverse, bioactive heterocycles.
Org. Biomol. Chem., 2016
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide H... more From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide HIV-1 integrase (IN) inhibitor was identified. Subsequent optimisation afforded an analogue exhibiting an IC50 value of 2.5 μM.
Organic & biomolecular chemistry, Jan 9, 2015
Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thi... more Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thirty five novel leucine-containing intermediate oxazoles and thiazoles were prepared in this study. This includes the first examples of the direct C-5 arylation of an amino acid dipeptide-derived oxazole. Moderate to excellent antibacterial activity was observed for all new compounds across Gram positive isolates with MICs ranging from 1-16 μg mL(-1). Results for Gram negative E. coli and A. baumannii were more variable, but MICs as low as 4 μg mL(-1) were returned for two examples. Significantly, the in vitro results with a fluoromethyl-oxazole derivative collectively represent the best obtained to date for a member of our binaphthyl peptide antimicrobials.
Tetrahedron, 2015
The allylation of indirubin produced the expected indolic N′-allylindirubin and N,N′-diallylindir... more The allylation of indirubin produced the expected indolic N′-allylindirubin and N,N′-diallylindirubin derivatives in moderate yields, together with the corresponding N-substituted isatin products. At higher temperatures, the base-initiated reaction with allylic halides yielded spiroindolinepyrido[1,2-a]indolediones in a one-pot cascade reaction sequence with yields of up to 70%. These readily accessed, new spiro compounds represent the first reported examples of indirubin participating in cascade reactions. Preliminary in vitro biological testing of some of the products indicated promising activity against some cancer cell lines and against Plasmodium falciparum for two spiro derivatives. Computational methods were used to gain a greater understanding of the UV/Vis spectroscopic data for the N′-substituted and N,N′-disubstituted indirubin derivatives.
Journal of Organometallic Chemistry, 2015
Arsenous chloride-free synthesis of cyclic tertiary organoarsines from arylarsine oxides and di-G... more Arsenous chloride-free synthesis of cyclic tertiary organoarsines from arylarsine oxides and di-Grignard reagents
Beilstein Journal of Organic Chemistry, 2015
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedd... more Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
Organic & Biomolecular Chemistry, 2015
Designed binaphthyl-based, cationic peptidomimetic antimicrobials targetingC. difficile, incorpor... more Designed binaphthyl-based, cationic peptidomimetic antimicrobials targetingC. difficile, incorporating a click-derived 1,2,3-triazole ester isostere at the C-terminus MICs of 4 μg mL−1against three human isolates ofC. difficile.
Tetrahedron, 2006
Synthesis of some cyclic indolic peptoids as potential antibacterials Synthesis of some cyclic in... more Synthesis of some cyclic indolic peptoids as potential antibacterials Synthesis of some cyclic indolic peptoids as potential antibacterials
Tetrahedron, 2008
As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold... more As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 µg/mL.
Organic Letters, 2008
Reagents and solvents were purchased reagent-grade and used without further purification. Toluene... more Reagents and solvents were purchased reagent-grade and used without further purification. Toluene and THF were distilled from sodium benzophenone ketyl. CH 2 Cl 2 was stored over CaCl 2 and distilled from CaH 2. [60]Fullerene was purchased from MER Corporation Tucson, Arizona AZ 85706 USA. All reactions were performed in standard glassware under an inert atmosphere of nitrogen. Flash column chromatography was performed using silica 60 (230-400 mesh, 0.040-0.063 mm) purchased from Merck. ESI SI-2 MS were recorded on a ThermoFinnigan LTQ (Waltham, MA) fitted with a conventional IonMax electrospray ionization source. Spectra were obtained by infusion of a standard solution (2:1 chloroform : methanol). Typical settings were spray voltages between 4-6 kV, capillary temperature 270 o C and sheath gas flow rates at 10 (arbitrary units). 1 H NMR spectra were acquired on a Varian Unity 300 or 500 spectrometer at 300.1 and 499.9 MHz respectively, or a Bruker DMX-600 spectrometer at 600.2 MHz. 13 C NMR spectra were acquired on Varian Unity 300 or 500 spectrometer at 75.4 and 125.0 MHz respectively, or a Bruker DMX-600 spectrometer at 150.9 MHz. Deuterated solvents were obtained commercially (Sigma-Aldrich or Cambridge) and were greater than 99.5 atom % d. All chemical shifts are reported relative to TMS (0.00).
The Journal of Organic Chemistry, 2013
The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot ... more The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a′]diindole, pyrido[1,2-a:3,4-b′]diindole and benzo[b]indolo[1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring Bhomologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through singlecrystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means.
European Journal of Medicinal Chemistry, 2011
The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C2s... more The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C2symmetric binaphthyl scaffold which holds two identical chains consisting of a short linker, a basic amino acid and a small hydrophobic side chain. Antibacterial activity is revealed for a number of derivatives down to an MIC of 2 µg/mL (2 µM) against Staphylococcus aureus-comparable to vancomycin, and an MIC of 31 µg/mL (31 µM) against some vancomycin resistant enterococcal strains.
European Journal of Medicinal Chemistry, 2009
An efficient synthesis of two new N-acetyl-4'-arylphenylalanines is described together with their... more An efficient synthesis of two new N-acetyl-4'-arylphenylalanines is described together with their incorporation in to a number of cationic peptoid antibacterial agents, one of which had an MIC of 7.8 μg/ mL against Staphylococcus aureus.
Chemical Communications, 2010
The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bio... more The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bioxirane, or three steps from 2,2'-biaziridine, both with exceptional enantiopurity
Chemical Communications, 2010
Table 1. Investigation into the Pd(II)-catalysed C-H activation of enamine 10, affording 2,3-disu... more Table 1. Investigation into the Pd(II)-catalysed C-H activation of enamine 10, affording 2,3-disubstituted indole 11.
Beilstein Journal of Organic Chemistry, 2012
The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobi... more The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2–4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.