Publications by authors named "Paul A Keller"

87 Publications

Cationic Peptidomimetic Amphiphiles Having a -Aryl- or -Naphthyl-1,2,3-Triazole Core Structure Targeting () : Synthesis, Antibacterial Evaluation, and an In Vivo Infection Model.

Antibiotics (Basel) 2021 Jul 26;10(8). Epub 2021 Jul 26.

School of Chemistry and Biomolecular Science, University of Wollongong, Wollongong, NSW 2522, Australia.

(also known as ) 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 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 -arytriazole or -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 -naphthyltriazole derivative was identified as a -selective antibacterial with MIC values of 8 µg/mL against strains ATCC 700057 and 132 (both ribotype 027). This compound displayed increased water solubility and reduced hemolytic activity (32 µg/mL) in an in vitro hemolysis assay and reduced cytotoxicity (CC 32 µg/mL against HEK293 cells) relative to lead compound . Compound exhibited mild efficacy (with 80% survival observed after 24 h compared to the DMSO control of 40%) in an in vivo murine model of infection by reducing the severity and slowing the onset of disease.
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http://dx.doi.org/10.3390/antibiotics10080913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388771PMC
July 2021

The Detosylation of Chiral 1,2-Bis(tosylamides).

J Org Chem 2021 Jul 21;86(13):9163-9180. Epub 2021 Jun 21.

School of Chemistry and Molecular Bioscience, Molecular Horizons, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.

The deprotection of chiral 1,2-bis(tosylamides) to their corresponding 1,2-diamines is mostly unsuccessful under standard conditions. In a new methodology, the use of Mg/MeOH with sufficient steric additions allows the facile synthesis of 1,2-diamines in 78-98% yields. These results are rationalized using density functional theory and the examination of inner and outer-sphere reduction mechanisms.
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http://dx.doi.org/10.1021/acs.joc.1c00359DOI Listing
July 2021

Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.

RSC Med Chem 2020 Dec 23;11(12):1413-1422. Epub 2020 Sep 23.

School of Chemistry and Molecular Bioscience, and Molecular Horizons Research Institute, University of Wollongong Wollongong 2522 NSW Australia

African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa. High-throughput screening identified the thiazolyl-benzothiophenamide to be active against the causative parasite, . This work establishes structure-activity relationships of , guiding the design of second generation derivatives. After screening against the clinically relevant species , the derivative was identified as a suitable candidate for further investigation.
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http://dx.doi.org/10.1039/d0md00277aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126881PMC
December 2020

Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles.

ACS Med Chem Lett 2021 Mar 3;12(3):413-419. Epub 2021 Feb 3.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.

Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer exhibited 4-8× increased efficacy against the pathogenic Gram-negative bacteria and (MIC = 2 μg/mL), while isomers , , and exhibited a 4× increase in activity against (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25-8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant , , and ).
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http://dx.doi.org/10.1021/acsmedchemlett.0c00611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957938PMC
March 2021

Design, Synthesis, and Biological Evaluation of Novel Fluorescent Probes Targeting the 18-kDa Translocator Protein.

ChemMedChem 2021 06 24;16(12):1902-1916. Epub 2021 Mar 24.

School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia.

A series of fluorescent probes from the 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-yl acetamides ligands featuring the 7-nitro-2-oxa-1,3-diazol-4-yl (NBD) moiety has been synthesized and biologically evaluated for their fluorescence properties and for their binding affinity to the 18-kDa translocator protein (TSPO). Spectroscopic studies including UV/Vis absorption and fluorescence measurements showed that the synthesized fluorescent probes exhibit favorable spectroscopic properties, especially in nonpolar environments. In vitro fluorescence staining in brain sections from lipopolysaccharide (LPS)-injected mice revealed partial colocalization of the probes with the TSPO. The TSPO binding affinity of the probes was measured on crude mitochondrial fractions separated from rat brain homogenates in a [ C]PK11195 radioligand binding assay. All the new fluorescent probes demonstrated moderate to high binding affinity to the TSPO, with affinity (K ) values ranging from 0.58 nM to 3.28 μM. Taking these data together, we propose that the new fluorescent probes could be used to visualize the TSPO.
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http://dx.doi.org/10.1002/cmdc.202000984DOI Listing
June 2021

Anti-cancer Evaluation of Depsides Isolated from Indonesian Folious Lichens: , and .

Biomolecules 2020 10 8;10(10). Epub 2020 Oct 8.

School of Chemistry & Molecular Bioscience and Molecular Horizons, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, NSW 2522, Australia.

Cancer is a serious health burden on global societies. The discovery and development of new anti-cancer therapies remains a challenging objective. Although it has been shown that lichen secondary metabolites may be potent sources for new anti-cancer agents, the Indonesian- grown folious lichens, and have not yet been explored. In this study exhaustive preparative high-performance liquid chromatography was employed to isolate the lichen constituents with spectroscopic and spectrometric protocols identifying nine depsides -, including the new methyl 4-formyl-2,3-dihydroxy-6-methylbenzoate . The cytotoxicity of the depsides towards cancer cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicated lowest toxicity of the depsides towards human A549 lung cancer cells. Importantly, the di-depsides (, and ) showed greatest toxicity, indicating that these structures are biologically more active than the mono-depsides against the HepG2 liver cancer, A549 lung cancer and HL-60 leukemia cell lines.
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http://dx.doi.org/10.3390/biom10101420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600581PMC
October 2020

The Cascade Reactions of Indigo with Propargyl Substrates for Heterocyclic and Photophysical Diversity.

Chemistry 2021 Feb 12;27(11):3708-3721. Epub 2021 Feb 12.

School of Chemistry & Molecular Bioscience, Molecular Horizons, Illawarra Health & Medical Research Institute, University of Wollongong, Northfields Avenue, 2522, Wollongong, NSW, Australia.

The synthesis of structurally diverse heterocycles for chemical space exploration was achieved via the cascade reactions of indigo with propargylic electrophiles. New pyrazinodiindolodione, naphthyridinedione, azepinodiindolone, oxazinoindolone and pyrrolodione products were prepared in one pot reactions by varying the leaving group (-Cl, -Br, -OMs, -OTs) or propargyl terminal functionality (-H, -Me, -Ph, -Ar). Mechanistic and density functional theory studies revealed that the unsaturated propargyl moiety can behave as an electrophile when aromatic terminal substitutions are made, and therefore competes with leaving group substitution for new outcomes. Selected products from the cascade reactions were investigated for their absorption and fluorescence properties, including transient absorption spectroscopy. This revealed polarity dependent excited state relaxation pathways, fluorescence, and triplet formation, thus highlighting these reactions as a means to access diverse functional materials rapidly.
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http://dx.doi.org/10.1002/chem.202003662DOI Listing
February 2021

The evolution of sexually dimorphic cuticular hydrocarbons in blowflies (Diptera: Calliphoridae).

J Evol Biol 2020 10 10;33(10):1468-1486. Epub 2020 Aug 10.

Centre for Sustainable Ecosystem Solutions, School of Earth, Atmospheric and Life Sciences, University of Wollongong, Wollongong, NSW, Australia.

Cuticular hydrocarbons (CHCs) are organic compounds found on the cuticles of all insects which can act as close-contact pheromones, while also providing a hydrophobic barrier to water loss. Given their widespread importance in sexual behaviour and survival, CHCs have likely contributed heavily to the adaptation and speciation of insects. Despite this, the patterns and mechanisms of their diversification have been studied in very few taxa. Here, we perform the first study of CHC diversification in blowflies, focussing on wild populations of the ecologically diverse genus Chrysomya. We convert CHC profiles into qualitative and quantitative traits and assess their inter- and intra-specific variation across 10 species. We also construct a global phylogeny of Chrysomya, onto which CHCs were mapped to explore the patterns of their diversification. For the first time, we demonstrate that blowflies express an exceptional diversity of CHCs, which have diversified in a nonphylogenetic and punctuated manner, are species-specific and sexually dimorphic. It is likely that both ecological and sexual selection have shaped these patterns of CHC diversification, and our study now provides a comprehensive framework for testing such hypotheses.
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http://dx.doi.org/10.1111/jeb.13685DOI Listing
October 2020

Major Transitions in Cuticular Hydrocarbon Expression Coincide with Sexual Maturity in a Blowfly (Diptera: Calliphoridae).

J Chem Ecol 2020 Jul 15;46(7):610-618. Epub 2020 Jul 15.

Centre for Sustainable Ecosystem Solutions, School of Earth, Atmospheric and Life Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.

In many animals, there is a prolonged pre-reproductive period prior to sexual maturity. To avoid premature mating attempts, it is common for phenotypic changes to occur during this period that signal the onset of reproductive viability. Among the insects, pre-reproductive phases can last for up to 50% of the adult lifespan, but little is known about the accompanying phenotypic changes that signal sexual maturity. Contact pheromones such as cuticular hydrocarbons (CHCs) may fulfil this role, as they are known to change rapidly with age in many insects. Despite this, few studies have investigated CHC development in the context of sexual maturity or considered differences in CHC development between sexes. The blowflies (Diptera: Calliphoridae) provide an ideal system for such studies because CHCs are known to change rapidly with age and likely play an important role in sexual behaviour. As such, using the small hairy maggot blowfly Chrysomya varipes, we investigate whether there are age- and sex-specific changes in CHCs over the course of adult blowfly maturation. We show that: (1) major qualitative transitions in CHC expression coincide with the onset of sexual maturity and (2) these changes occur more slowly in females - in line with their extended pre-reproductive phase. We suggest that CHCs may play an important role in signalling sexual maturity in the small hairy maggot blowfly and that this species will likely serve as a useful model for understanding the complex ontogeny of cuticular hydrocarbons in insects.
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http://dx.doi.org/10.1007/s10886-020-01194-2DOI Listing
July 2020

Stimuli-Responsive Cycloaurated "OFF-ON" Switchable Anion Transporters.

Angew Chem Int Ed Engl 2020 09 11;59(40):17614-17621. Epub 2020 Aug 11.

School of Chemistry, The University of Sydney, Sydney, New South Wales, 2006, Australia.

Anion transporters have shown potential application as anti-cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are "switched on" in situ in the presence of the reducing agent GSH by decomplexation of gold. GSH is found in higher concentrations in tumors than in healthy tissue and hence this approach offers a strategy to target these systems to tumors.
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http://dx.doi.org/10.1002/anie.202006392DOI Listing
September 2020

Perylene-Monoimides: Singlet Fission Down-Conversion Competes with Up-Conversion by Geminate Triplet-Triplet Recombination.

J Phys Chem A 2020 Jul 7;124(28):5727-5736. Epub 2020 Jul 7.

Department of Chemistry and Pharmacy & Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Egerlandstrasse 3, 91058 Erlangen, Germany.

Triplet-excited-state energies of perylene-monoimides (PMIs) lie in the range 1.12 eV ± 2 meV when compared to singlet-excited-state energies of about 2.39 eV ± 2 meV; therefore, the corresponding naphthalene-linked was investigated as a novel singlet-fission (SF) material. Ultrafast transient absorption measurements demonstrated the (SS)-to-(TT) transformation and the involvement of a mediating step in the overall (TT) formation. The intermediate is a charge-transfer state that links the initial (SS) with the final (TT), and imposes charge-transfer character on both, which are thus denoted (SS) and (TT). At room temperature, the decorrelation and stability of (TT) is affected by the geminate triplet-triplet recombination (G-TTR) of the two triplets. Independent confirmation for G-TTR to afford up-converted (SS) in fsTA and nsTA measurements with , came from probing (T)s in triplet-triplet annihilation up-conversion (TTA-UC). The G-TTR channel, active in the at room temperature, is suppressed by working at either low temperatures (∼140 K) or in polar solvents (benzonitrile): Both scenarios assist in stabilizing (TT). As a consequence, the triplet quantum yields are 4.2% and 14.9% at room temperature and 140 K, respectively, in 2-methyltetrahydrofuran.
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http://dx.doi.org/10.1021/acs.jpca.0c04091DOI Listing
July 2020

How To Make Nitroaromatic Compounds Glow: Next-Generation Large X-Shaped, Centrosymmetric Diketopyrrolopyrroles.

Angew Chem Int Ed Engl 2020 Sep 10;59(37):16104-16113. Epub 2020 Jul 10.

Institute of Organic Chemistry, PAS. 44/52 Kasprzaka, 01-224, Warsaw, Poland.

Red-emissive π-expanded diketopyrrolopyrroles (DPPs) with fluorescence reaching λ=750 nm can be easily synthesized by a three-step strategy involving the preparation of diketopyrrolopyrrole followed by N-arylation and subsequent intramolecular palladium-catalyzed direct arylation. Comprehensive spectroscopic assays combined with first-principles calculations corroborated that both N-arylated and fused DPPs reach a locally excited (S ) state after excitation, followed by internal conversion to states with solvent and structural relaxation, before eventually undergoing intersystem crossing. Only the structurally relaxed state is fluorescent, with lifetimes in the range of several nanoseconds and tens of picoseconds in nonpolar and polar solvents, respectively. The lifetimes correlate with the fluorescence quantum yields, which range from 6 % to 88 % in nonpolar solvents and from 0.4 % and 3.2 % in polar solvents. A very inefficient (T ) population is responsible for fluorescence quantum yields as high as 88 % for the fully fused DPP in polar solvents.
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http://dx.doi.org/10.1002/anie.202005244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689858PMC
September 2020

Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action.

J Med Chem 2020 03 20;63(6):3317-3326. Epub 2020 Feb 20.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.

The design of three dual-tailed sulfonamide series , , and as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma ( in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (, , and ) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds - and were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. and showed significant efficacy when compared to the clinically used drug dorzolamide.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02090DOI Listing
March 2020

Regioselective convergent synthesis of 2-arylidene thiazolo[3,2-]pyrimidines as potential anti-chikungunya agents.

RSC Adv 2020 Jan 31;10(9):5191-5195. Epub 2020 Jan 31.

School of Chemistry & Molecular Bioscience, Molecular Horizons, University of Wollongong, Illawarra Health & Medical Research Institute Wollongong NSW 2522 Australia

Convergent and convenient regioselective synthesis of novel thiazolo[2,3-]pyrimidine derivatives was accomplished using the one-pot reaction of 6-ethylthiouracil, bromoacetic acid, anhydrous sodium acetate, acetic anhydride, acetic acid and suitable aldehyde. X-ray crystallographic study reveals the presence of the configuration of only one regioisomer confirmed by computational studies as being the most likely isomer present.
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http://dx.doi.org/10.1039/d0ra00257gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9049071PMC
January 2020

Vascular Epiphytic Medicinal Plants as Sources of Therapeutic Agents: Their Ethnopharmacological Uses, Chemical Composition, and Biological Activities.

Biomolecules 2020 01 24;10(2). Epub 2020 Jan 24.

School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, NSW 2522, Australia.

This is an extensive review on epiphytic plants that have been used traditionally as medicines. It provides information on 185 epiphytes and their traditional medicinal uses, regions where Indigenous people use the plants, parts of the plants used as medicines and their preparation, and their reported phytochemical properties and pharmacological properties aligned with their traditional uses. These epiphytic medicinal plants are able to produce a range of secondary metabolites, including alkaloids, and a total of 842 phytochemicals have been identified to date. As many as 71 epiphytic medicinal plants were studied for their biological activities, showing promising pharmacological activities, including as anti-inflammatory, antimicrobial, and anticancer agents. There are several species that were not investigated for their activities and are worthy of exploration. These epipythes have the potential to furnish drug lead compounds, especially for treating cancers, and thus warrant indepth investigations.
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http://dx.doi.org/10.3390/biom10020181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072150PMC
January 2020

Anti-Infective and Anti-Cancer Properties of the Species: Their Ethnomedicinal Uses, Alkaloid Diversity, and Pharmacological Activities.

Molecules 2019 Dec 3;24(23). Epub 2019 Dec 3.

School of Chemistry & Molecular Bioscience and Molecular Horizons, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, NSW 2533, Australia.

species have been a valuable source of anti-infective and anticancer agents. However, only limited evaluations of their alkaloids have been carried out. This review collates and evaluates the biological data from extracts and purified isolates for their anti-infective and anti-cancer activities. An isoquinoline backbone is a major structural alkaloid moiety of the genus, and more than 83 alkaloids have been isolated from this genus alone. Crude extracts of genus are reported with moderate activities against showing larvicidal activities. However, no pure compounds from the genus were tested against the parasite. The methanol extract of showed apparent antimicrobial activities. The isolated alkaloids from this genus including liriodenine, anonaine, asimilobine showed sensitivity against Other alkaloids such as (+)-Xylopine and isocoreximine indicated significant anti-cancer activity against A549 and K-562 cell lines, respectively. This review revealed that the alkaloids from genus are rich in structural diversity and pharmacological activities. Further exploration of this genus and their alkaloids has potential for developing novel anti-infective and anticancer drugs.
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http://dx.doi.org/10.3390/molecules24234419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930583PMC
December 2019

Synthesis and Density Functional Theory Studies of Azirinyl and Oxiranyl Functionalized Isoindigo and (3,3')-3,3'-(ethane-1,2-diylidene)bis(indolin-2-one) Derivatives.

Molecules 2019 Oct 10;24(20). Epub 2019 Oct 10.

School of Chemistry and Molecular Biosciences, Molecular Horizons, Illawarra Health and Medical Research Institute University of Wollongong, Wollongong, New South Wales 2522, Australia.

The design and synthesis of functionalized isoindigo compounds by reaction of isoindigo with ()-glycidyl tosylate, epibromohydrin, 2-(bromomethyl)-1-(arylsulfonyl)aziridine, and 2-(bromomethyl)-1-(alkylsulfonyl)aziridine in the presence of MeONa proceed under mild conditions in moderate yields. (3,3')-3,3'-(Ethane-1,2-diylidene)bis(1-(oxiran-2-ylmethyl)indolin-2-one), with an extended central olefin π-conjugated moiety was also reacted with methyl-oxiranes to give the corresponding -disubstituted derivative. Calculations with DFT and TD-DFT of hypothetical isoindigo-thiophene DA molecules with various electron withdrawing substituents, including aziridine, oxirane, nitrile, carbonyl, and sulfonate, indicated that the proximity and strength of the functional group have a significant effect on the HOMO, LUMO, vertical excitation energy, and oscillator strength of the π-π* transitions.
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http://dx.doi.org/10.3390/molecules24203649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832541PMC
October 2019

Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1,3']-3-Aryl-2,2'-diindol-3'-ones.

J Org Chem 2019 09 15;84(17):11228-11239. Epub 2019 Aug 15.

School of Chemistry & Molecular Bioscience, Molecular Horizons , University of Wollongong, and Illawarra Health & Medical Research Institute , Wollongong , New South Wales 2522 , Australia.

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 [1,3']-3-substituted 2,2'-diindol-3'-ones were synthesized by this methodology, with several showing submicromolar inhibition and exquisite selectivity against parasites (3D7 and Dd2 strains) . This work demonstrates the utility of indigo dye as a highly versatile scaffold for the synthesis of structurally diverse, bioactive heterocycles.
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http://dx.doi.org/10.1021/acs.joc.9b01442DOI Listing
September 2019

Alkaloids from the root of Indonesian L.

Nat Prod Res 2021 Feb 8;35(3):481-489. Epub 2019 Jul 8.

School of Chemistry & Molecular Bioscience and Molecular Horizons, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, NSW, Australia.

L. has been used traditionally in Indonesia to treat disease. Phytochemical studies on the alkaloid fractions from the root of L. from Malang-Indonesia resulted in the isolation of an unreported benzylisoquinoline alkaloid (+)-xylopine as well as four known alkaloids (-). The crude methanol extract and alkaloid fractions were tested against K1 and against bacteria (, , , , Methicillin-resistant ) with insignificant activities (MIC > 32 µg/mL). Individual alkaloids were tested against a human suspension cancer cell line (HL-60 leukemia cells) and two human fibroblastic cancer cell lines (A549 lung cancer cells and HepG2 liver cancer cells) in which compound as the most toxic alkaloid with IC values ranging from 20 to 80 µM.
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http://dx.doi.org/10.1080/14786419.2019.1638380DOI Listing
February 2021

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model.

Eur J Med Chem 2019 May 1;170:203-224. Epub 2019 Mar 1.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address:

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 μg/mL against methicillin-resistant Staphylococcus aureus and 8 μg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 μg/mL), Pseudomonas aeruginosa (8 μg/mL) and Klebsiella pneumoniae (16 μg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.068DOI Listing
May 2019

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies.

Eur J Med Chem 2019 Apr 13;168:386-404. Epub 2019 Feb 13.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address:

Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 μg/mL) and Gram-negative (Escherichia coli - MIC = 4 μg/mL) pathogenic bacteria.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.013DOI Listing
April 2019

Photoprotection enhanced by red cell wall pigments in three East Antarctic mosses.

Biol Res 2018 Nov 21;51(1):49. Epub 2018 Nov 21.

Centre for Sustainable Ecosystem Solutions, School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia.

Background: Antarctic bryophytes (mosses and liverworts) are resilient to physiologically extreme environmental conditions including elevated levels of ultraviolet (UV) radiation due to depletion of stratospheric ozone. Many Antarctic bryophytes synthesise UV-B-absorbing compounds (UVAC) that are localised in their cells and cell walls, a location that is rarely investigated for UVAC in plants. This study compares the concentrations and localisation of intracellular and cell wall UVAC in Antarctic Ceratodon purpureus, Bryum pseudotriquetrum and Schistidium antarctici from the Windmill Islands, East Antarctica.

Results: Multiple stresses, including desiccation and naturally high UV and visible light, seemed to enhance the incorporation of total UVAC including red pigments in the cell walls of all three Antarctic species analysed. The red growth form of C. purpureus had significantly higher levels of cell wall bound and lower intracellular UVAC concentrations than its nearby green form. Microscopic and spectroscopic analyses showed that the red colouration in this species was associated with the cell wall and that these red cell walls contained less pectin and phenolic esters than the green form. All three moss species showed a natural increase in cell wall UVAC content during the growing season and a decline in these compounds in new tissue grown under less stressful conditions in the laboratory.

Conclusions: UVAC and red pigments are tightly bound to the cell wall and likely have a long-term protective role in Antarctic bryophytes. Although the identity of these red pigments remains unknown, our study demonstrates the importance of investigating cell wall UVAC in plants and contributes to our current understanding of UV-protective strategies employed by particular Antarctic bryophytes. Studies such as these provide clues to how these plants survive in such extreme habitats and are helpful in predicting future survival of the species studied.
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http://dx.doi.org/10.1186/s40659-018-0196-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247747PMC
November 2018

Cascade reactions of indigo with oxiranes and aziridines: efficient access to dihydropyrazinodiindoles and spiro-oxazocinodiindoles.

Org Biomol Chem 2018 08;16(33):6006-6016

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

The base-initiated alkylation of the abundant natural dye indigo 1 with ring-strained electrophiles results in the unprecedented, one-pot synthesis of functionalised dihydropyrazino[1,2-a:4,3-a']diindoles, dihydroepoxy[1,5]oxazocino[5,4-a:3,2-b']diindoles, and dihydrodiazepino[1,2-a:4,3-a']diindoles, resulting from intramolecular ring opening-expansion cyclisation processes of their parent oxiranes and aziridines. Regiochemical and stereochemical aspects of the reactions are reported together with integrated mechanistic proposals. This new indigo cascade chemistry should have broad applicability in the synthesis of chemical architectures, not readily-accessible by other means. The three-step synthesis of the useful synthetic precursor (R)-2-(chloromethyl)-1-tosylaziridine 14 is also described. Initial biological activity investigations into these new 2,2'-dindolyl-based heterocyclic derivatives revealed potent, selective antiplasmodial activity in vitro for several isolated structures, with IC50 values as low as 76.6 nM for (±)-8, while demonstrating low human cell toxicity.
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http://dx.doi.org/10.1039/c8ob00865eDOI Listing
August 2018

Phytochemical studies on the Australian native plant species and D.Don.

Nat Prod Res 2019 Jul 11;33(14):1997-2003. Epub 2018 Jun 11.

a School of Chemistry , University of Wollongong , Wollongong , Australia.

In ongoing investigations into colours in Nature, the chemical constituents from the flowers and D.Don grown in Australia are reported. Eight known secondary metabolites were isolated from the flower including isosalipurposide () which may be responsible for their distinctive colouration. Nine secondary metabolites were isolated from the D.Don flower including the new phenylethanoid β-D-glucopyranose (). All isolated compounds were inactive against bacteria tested at concentration of 32 μg/mL.
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http://dx.doi.org/10.1080/14786419.2018.1483922DOI Listing
July 2019

An improved synthesis of pyrido[2,3-d]pyrimidin-4(1H)-ones and their antimicrobial activity.

Org Biomol Chem 2018 05;16(18):3389-3395

School of Chemistry, University of Wollongong, Wollongong 2522, New South Wales, Australia.

The screening of a small library of diverse chemical structures resulted in the identification of 2-thioxodihydropyrido[2,3-d]pyrimidine 10a as having broad spectrum antibacterial activity (MIC 0.49-3.9 μg mL-1), and reasonable antifungal activity (MIC 31.25 μg mL-1). An expeditious synthesis of 10a was optimized by varying solvents, catalysts and the use of microwave irradiation with the best conditions using DMF as a solvent, I2 (10 mol%) and a 30 minutes reaction time compared to 15 h for classic conventional heating. The pharmacokinetic properties and calculation of drug likeness of 10a suggested good traditional drug-like properties and led to the synthesis of a small library with seven compounds 10a and 10d-i showing broad antimicrobial activity (MIC = 0.49-7.81 μg mL-1) and selectivity indices of more than 5.6 against the normal colon cell line (CCD-33Co). The antifungal activity of compounds 10d-i was moderate to strong with MIC values of 1.95-15.63 μg mL-1.
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http://dx.doi.org/10.1039/c8ob00627jDOI Listing
May 2018

Body Odor and Sex: Do Cuticular Hydrocarbons Facilitate Sexual Attraction in the Small Hairy Maggot Blowfly?

J Chem Ecol 2018 Mar 15;44(3):248-256. Epub 2018 Mar 15.

Centre for Sustainable Ecosystem Solutions, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.

Cuticular hydrocarbons (CHCs) play an important role as contact pheromones in insects, particularly in flies. However, for many fly taxa our understanding of the importance of CHCs in sexual communication is limited. Within the family Calliphoridae (blowflies), sex-specific differences in CHCs have been reported for several species, but there is no evidence that CHCs facilitate sexual behavior. In order to elucidate the function of CHCs in Calliphoridae, studies combining behavioral and chemical analyses are required. The present study used gas chromatography/mass spectrometry, along with behavioral assays, to assess whether CHCs facilitate sexual attraction in the small hairy maggot blowfly, Chrysomya varipes. The specific aims were to: 1) determine if CHCs differ between the sexes and 2) assess whether flies exhibit positive chemotaxis to CHCs of the opposite sex. Fifty-two hydrocarbons common to both sexes were identified, and quantitative differences for numerous CHCs were observed between the sexes. However, behavioral assays provided no evidence that flies were attracted to CHCs of the opposite sex, challenging the hypothesis that CHCs facilitate sexual attraction in Ch. varipes. In contrast to other blowflies, Ch. varipes males invest heavily in courtship displays and ornamentation, so we speculate that visual communication in this species may have relaxed sexual selection for chemical communication. More broadly, our findings support suggestions that CHCs may not always facilitate insect sexual communication.
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http://dx.doi.org/10.1007/s10886-018-0943-3DOI Listing
March 2018

Antarctic Moss Biflavonoids Show High Antioxidant and Ultraviolet-Screening Activity.

J Nat Prod 2017 08 7;80(8):2224-2231. Epub 2017 Aug 7.

School of Chemistry, UNSW , Sydney, NSW 2052, Australia.

Ceratodon purpureus is a cosmopolitan moss that survives some of the harshest places on Earth: from frozen Antarctica to hot South Australian deserts. In a study on the survival mechanisms of the species, nine compounds were isolated from Australian and Antarctic C. purpureus. This included five biflavonoids, with complete structural elucidation of 1 and 2 reported here for the first time, as well as an additional four known phenolic compounds. Dispersion-corrected DFT calculations suggested a rotational barrier, leading to atropisomerism, resulting in the presence of diastereomers for compound 2. All isolates absorbed strongly in the ultraviolet (UV) spectrum, e.g., biflavone 1 (UV-A, 315-400 nm), which displayed the strongest radical-scavenging activity, 13% more efficient than the standard rutin; p-coumaric acid and trans-ferulic acid showed the highest UV-B (280-315 nm) absorption. The more complex and abundant 1 and 2 presumably have dual roles as both UV-screening and antioxidant compounds. They are strongly bound to Antarctic moss cell walls as well as located inside the cells of moss from both locations. The combined high stability and photoprotective abilities of these isolates may account for the known resilience of this species to UV-B radiation and its survival in some of the toughest locations in the world.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00085DOI Listing
August 2017

Phytochemical Studies on Two Australian Anigozanthos Plant Species.

J Nat Prod 2017 07 6;80(7):2141-2145. Epub 2017 Jul 6.

School of Chemistry, University of Wollongong , Wollongong, NSW 2522, Australia.

Phytochemical studies of two Australian Anigozanthos (kangaroo paw) species, A. rufus and A. pulcherrimus, resulted in the identification of 13 secondary metabolites. 2-Amino-6-O-p-coumarylheptanedioic acid (3) and chalcone-5'-O-(4-O-p-coumaryl)-O-β-d-glucopyranoside (12) are reported as new compounds and are accompanied by nine flavonoids (2, 5-11, 13) and two anthocyanins (1, 4). Compounds 1 and 4 were isolated as red solids from A. rufus and are likely responsible for the coloration of the flowers. Compounds 1, 3, and 6 showed weak antimicrobial activities against Acinetobacter baumannii ATCC 19606 at concentrations of 52.4, 94.9, and 53.9 μM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00063DOI Listing
July 2017

Molecular Docking Studies to Explore Potential Binding Pockets and Inhibitors for Chikungunya Virus Envelope Glycoproteins.

Interdiscip Sci 2018 Sep 11;10(3):515-524. Epub 2017 Mar 11.

School of Chemistry, University of Wollongong, Wollongong, 2522, Australia.

The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies. In addition to reproducing previously reported examples, new binding pockets were identified, e.g., Pocket 2 in the 3N40, and Pocket 2 and Pocket 3 in the 3N42. Convergences in conformational sampling in docking using AutoDock Vina were evaluated. An analysis of docking results was carried out to understand interactions of the envelope glycoproteins complexes. Some key residues for interactions, for example Gly91 and His230, are identified as possessing important roles in the fusion process.
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http://dx.doi.org/10.1007/s12539-016-0209-0DOI Listing
September 2018

Anti-inflammatory, Anti-bacterial and Anti-acetylcholinesterase Activities of two Isoquinoline Alkaloids-Scoulerine and Cheilanthifoline.

Nat Prod Commun 2016 Dec;11(12):1801-1804

Corydalis plants containing isoquinoline alkaloids are reported to possess promising phamacological properties for the treatment of important diseases including cancer, inflammation, Alzheimer's disease and microbial infections. As part of a wider program investigating Bhutanese medicinal plants,.we have previously identified eight isoquinoline alkaloids from C. dubia. Out of these, we report here on two of the major alkaloids, scoulerine (1) and cheilanthifoline (2) and their inhibitory activities against acetylcholinesterase (anti-AChE),-tumor necrosis factor alpha (anti TNF-α) and a bacteial strain, Helicobacterpylori. Both alkaloids showed weak anti TNF-α and antibacterial activities. However, the anti-AChE activity of scoulerine (1) was promising as it-significantly inhibited AChE with a minimum inhibitory requirement (MIR) value of 0.0015 nmol, which was two-fold better than the reference drug, galanthamine (MIR value of 0.003 nmol). As there are limited.anti-Alzheimer's chemotherapeutics, scoulerine (1) is worthy of further exploration, including lead optimization, structure-activity-relationship studies, analog development,.pharmacodynanics and in vivo animal studies.
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December 2016
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