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1.
Eur J Med Chem ; 276: 116677, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39024967

RESUMO

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

2.
Org Biomol Chem ; 21(29): 5970-5976, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37431835

RESUMO

Herein the synthesis of 1,8-naphthalimides functionalised as the 3,4-dihydroxy-1,8-naphthalimide (catechol, Nap-Cat) and the corresponding 15-crown-5 (Nap-Crown) is reported. These compounds represent the first examples where these two recognition groups are directly incorporated into the 1,8-naphthalimide ring system. Both Nap-Cat and Nap-Crown were evaluated for their capacity to respond to analytes such as H2O2 (a mimic for cellular oxidation) and metal ions (as elements of environmental and physiological interest). While slow oxidation was observed for Nap-Cat upon prolonged exposure to H2O2, no significant changes in photophysical properties were observed upon treatment of Nap-Crown with metal ions.

3.
J Med Chem ; 66(5): 3540-3565, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36812492

RESUMO

There is an urgent need to populate the antimalarial clinical portfolio with new candidates because of resistance against frontline antimalarials. To discover new antimalarial chemotypes, we performed a high-throughput screen of the Janssen Jumpstarter library against the Plasmodium falciparum asexual blood-stage parasite and identified the 2,3-dihydroquinazolinone-3-carboxamide scaffold. We defined the SAR and found that 8-substitution on the tricyclic ring system and 3-substitution of the exocyclic arene produced analogues with potent activity against asexual parasites equivalent to clinically used antimalarials. Resistance selection and profiling against drug-resistant parasite strains revealed that this antimalarial chemotype targets PfATP4. Dihydroquinazolinone analogues were shown to disrupt parasite Na+ homeostasis and affect parasite pH, exhibited a fast-to-moderate rate of asexual kill, and blocked gametogenesis, consistent with the phenotype of clinically used PfATP4 inhibitors. Finally, we observed that optimized frontrunner analogue WJM-921 demonstrates oral efficacy in a mouse model of malaria.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Animais , Camundongos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Plasmodium falciparum , Homeostase , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia
4.
ChemMedChem ; 17(18): e202200306, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35906744

RESUMO

Plasmepsin X (PMX) is an aspartyl protease that processes proteins essential for Plasmodium parasites to invade and egress from host erythrocytes during the symptomatic asexual stage of malaria. PMX substrates possess a conserved cleavage region denoted by the consensus motif, SFhE (h=hydrophobic amino acid). Peptidomimetics reflecting the P3 -P1 positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P1 position, di-substitution at the ß-carbon of the P2 moiety and a hydrophobic P3 group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest asexual P. falciparum parasites at the schizont stage by impairing PMX substrate processing. Overall, the peptidomimetics described will assist in further understanding PMX substrate specificity and have the potential to act as a template for future antimalarial design.


Assuntos
Antimaláricos , Antagonistas do Ácido Fólico , Malária Falciparum , Peptidomiméticos , Aminoácidos , Antimaláricos/química , Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases , Carbono , Humanos , Malária Falciparum/tratamento farmacológico , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Plasmodium falciparum/metabolismo , Inibidores de Proteases/química , Proteínas de Protozoários
5.
J Org Chem ; 87(9): 6492-6498, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35442025

RESUMO

4-Amino-1,8-naphthalimides, potentially useful fluorescent probes in biological applications, are prepared via Ni(cod)2/IPr-catalyzed cross-couplings between 4-chloro-1,8-naphthalimide electrophiles and α,α,α-trisubstituted, primary alkylamines at room temperature. This method represents the first synthesis of 4-amino-1,8-naphthalimides using Ni-catalyzed C-N cross-coupling and provides the first examples of 4-amino-1,8-naphthalimides incorporating such bulky primary alkylamines, thereby highlighting the utility of Ni-catalyzed processes in synthesizing naphthalimide scaffolds that were inaccessible using established methods (SNAr; Pd or Cu catalysis).


Assuntos
Naftalimidas , Níquel , Catálise , Temperatura
6.
Bioorg Chem ; 117: 105359, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34689083

RESUMO

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Aminação , Compostos de Anilina/uso terapêutico , Animais , Antimaláricos/uso terapêutico , Feminino , Humanos , Malária/parasitologia , Camundongos , Plasmodium/fisiologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/fisiologia , Quinazolinas/uso terapêutico
7.
Langmuir ; 37(30): 9202-9214, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34286574

RESUMO

The effect of support hydrophobicity on lipase activity and substrate selectivity was investigated with and without Triton X-100 (TX-100). Lipases from Thermomyces lanuginosa (TL) and Alcaligenes sp. (QLM) were immobilized on graphene oxide (GO) and a range of chemically reduced graphene oxides (CRGOs) with different levels of surface hydrophobicity. Activity assays using 4-hydroxy-N-propyl-1,8-naphthalimide (NAP) esters of varying chain lengths (NAP-butyrate (NAP-B), NAP-octanoate (NAP-O), and NAP-palmitate (NAP-P)) showed that the activity of immobilized QLM and TL decreased by more than 60% on GO and 80% on CRGO (2 h), with activity decreasing further as surface hydrophobicity of the CRGOs increased. Across the hydrophobicity range of GO/CRGOs, the substrate selectivity of QLM shifted from more readily hydrolyzing NAP-P to NAP-B, while TL retained its substrate selectivity for NAP-O. Lipase TL was also shown to desorb from GO and 2 h CRGO when mixed with NAP-O and NAP-P, whereas QLM did not. Circular dichroism analyses of the lipase α-helix content correlate to the observed activity data, with decreases in the α-helical content (40% in TL and 20% in QLM relative to free lipase) consistent with decreases in activity after immobilization on GO. α-Helical content decreased even further as the surface hydrophobicity of CRGOs increased. Attenuated total reflectance-Fourier transform infrared spectroscopy also showed significant changes to the lipase secondary structure upon immobilization. The addition of TX-100 into the activity assay modified the substrate selectivity of immobilized QLM, improving the activity against NAP-O (90%) and NAP-P (67%) compared to the activity measured without TX-100. It was shown that TX-100 primarily affected the activity of QLM by interacting with the ester substrate and the lipase itself. This study provides an improved understanding of how support hydrophobicity and the presence of TX-100 can affect activity/selectivity of lipases immobilized on hydrophobic supports.


Assuntos
Grafite , Lipase , Enzimas Imobilizadas , Octoxinol , Óxidos
8.
Cells ; 10(6)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203745

RESUMO

Methodology to access fluorescent 3-amido-1,8-naphthalimides using direct Buchwald-Hartwig amidation is described. The protocol was successfully used to couple a number of substrates (including an alkylamide, an arylamide, a lactam and a carbamate) to 3-bromo-1,8-naphthalimide in good yield. To further exemplify the approach, a set of scriptaid analogues with amide substituents at the 3-position were prepared. The new compounds were more potent than scriptaid at a number of histone deacetylase (HDAC) isoforms including HDAC6. Activity was further confirmed in a whole cell tubulin deacetylation assay where the inhibitors were more active than the established HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds make them amenable to cellular imaging studies and theranostic applications.


Assuntos
Inibidores de Histona Desacetilases/química , Hidroxilaminas/química , Naftalenos/química , Quinolinas/química , Acetilação , Amidas/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Naftalimidas/química
9.
J Org Chem ; 85(12): 7986-7999, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32426981

RESUMO

The Buchwald-Hartwig cross-coupling reaction between 4-methylumbelliferone-derived nonaflates with amides, carbamates, and sulfonamides is described. A wide variety of N-substituted 7-amino coumarin analogues was prepared in good to excellent yields. The photophysical properties of aqueous-soluble derivatives were determined, and they displayed auxochrome-based variations. Gram-scale synthesis provided an acrylamide analogue, which was used to fabricate a fluorescent poly(2-hydroxylethyl methacrylate) (pHEMA) hydrogel that was resistant to leaching in ultrapure H2O. We envisage that our reported protocol to access 7-amino-4-methylcoumarin derivatives will find use toward the development of new fluorescent coumarin-based probes by researchers in the field.

10.
Chem Commun (Camb) ; 56(50): 6866-6869, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32432616

RESUMO

An efficient and functional group tolerant route to access hydroxy 1,8-naphthalimides has been used to synthesise a range of mono- and disubstituted hydroxy-1,8-naphthalimides with fluorescence emissions covering the visible spectrum. The dialkoxy substituted compounds prepared possess high quantum yields (up to 0.95) and long fluorescent lifetimes (up to 14 ns). The method has been used to generate scriptaid analogues that successfully inhibit HDAC6 in vitro with tubulin acetylation assays confirming that these compounds are more effective than tubastatin.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Naftalimidas/farmacologia , Tubulina (Proteína)/metabolismo , Células A549 , Acetilação/efeitos dos fármacos , Cor , Fluorescência , Inibidores de Histona Desacetilases/química , Humanos , Naftalimidas/química
11.
J Med Chem ; 62(23): 10526-10562, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31385706

RESUMO

Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Plasmodium/efeitos dos fármacos , Antimaláricos/farmacologia , Descoberta de Drogas , Humanos , Estrutura Molecular , Plasmodium/crescimento & desenvolvimento , Plasmodium/patogenicidade
12.
Eur J Med Chem ; 162: 321-333, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448419

RESUMO

Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6 > 500) and potency (HDAC6 IC50 < 5 nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to ΦF = 0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Hidroxilaminas/química , Quinolinas/química , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Citoplasma/metabolismo , Diagnóstico por Imagem/métodos , Fluorescência , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Hidroxilaminas/síntese química , Hidroxilaminas/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Peixe-Zebra/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-30559138

RESUMO

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound's capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.


Assuntos
Compostos de Anilina/farmacologia , Antiparasitários/farmacologia , Babesia bovis/efeitos dos fármacos , Cryptosporidium parvum/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinazolinas/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Linhagem Celular , Cloroquina/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Testes de Sensibilidade Parasitária , Ratos , Ratos Sprague-Dawley
14.
Eur J Med Chem ; 160: 9-22, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30316060

RESUMO

The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MIC = 0.25 µg/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion. Two fluorescent analogues (compound 29 with 4-amino-naphthalimide and 34 with 4-nitrobenz-2-oxa-1,3-diazole fluorophores) with good activity (MIC = 0.5 µg/mL against MRSA) were also constructed and confocal microscopy studies indicate that the primary site of interaction for this family of compounds is the bacterial membrane.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Norbornanos/farmacologia , Peptidomiméticos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Staphylococcus aureus Resistente à Meticilina/citologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Norbornanos/química , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade
15.
Cell Rep ; 16(11): 2802-2810, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27626651

RESUMO

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.


Assuntos
Proteínas Correpressoras/metabolismo , Metabolismo Energético , Histona Desacetilases/metabolismo , Metabolismo dos Lipídeos , Animais , Domínio Catalítico , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos , Mutação/genética , Oxirredução , Condicionamento Físico Animal , Ligação Proteica/efeitos dos fármacos , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Transcrição Gênica/efeitos dos fármacos
16.
Biochimie ; 128-129: 127-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27478942

RESUMO

Research using 1,8-naphthalimide derivatives has expanded rapidly in recent years owing to their cell-permeable nature, ability to target certain cellular locations and fluorescent properties. Here we describe the synthesis of three new esters of 4-hydroxy-N-propyl-1,8-naphthalimide (NAP) and the development of a simple and sensitive assay protocol to measure the activity of carboxylester hydrolases. The NAP fluorophore was esterified with short (butyrate), medium (octanoate) and long (palmitate) chain fatty acids. The esters were spectroscopically characterised and their properties investigated for their suitability as assay substrates. The esters were found to be relatively stable under the conditions of the assay and levels of spontaneous hydrolysis were negligible. Non-specific hydrolysis by proteins such as bovine serum albumin was also minimal. A simple and rapid assay methodology was developed and used to analyse a range of commercially available enzymes that included enzymes defined as lipases, esterases and phospholipases. Clear differences were observed between the enzyme classes with respect to the hydrolysis of the various chain length esters, with lipases preferentially hydrolysing the medium chain ester, whereas esterases reacted more favourably with the short ester. The assay was found to be highly sensitive with the fluorophore detectable to the low nM range. These esters provide alternate substrates from established coumarin-based fluorophores, possessing distinctly different excitation (447 nm) and emission (555 nm) optima. Absorbing at 440-450 nm also offers the flexibility of analysis by UV-visible spectrophotometry. This represents the first instance of a naphthalimide-derived compound being used to analyse these enzymes.


Assuntos
Esterases/metabolismo , Ésteres/química , Fluorescência , Lipase/metabolismo , Naftalimidas/química , Ascomicetos/enzimologia , Proteínas de Bactérias/metabolismo , Candida/enzimologia , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Esterases/química , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Corantes Fluorescentes/química , Proteínas Fúngicas/metabolismo , Cinética , Lipase/química , Pseudomonas fluorescens/enzimologia , Espectrofotometria
17.
Chemistry ; 21(42): 14987-95, 2015 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-26334026

RESUMO

Incorporating phenylpyridine- and triazolylpyridine-based ligands decorated with methylsulfonate or tetraethylene glycol (TEG) groups, a series of iridium(III) complexes has been created for green and blue electrogenerated chemiluminescence under analytically useful aqueous conditions, with tri-n-propylamine as a coreactant. The relative electrochemiluminescence (ECL) intensities of the complexes were dependent on the sensitivity of the photodetector over the wavelength range and the pulse time of the applied electrochemical potential. In terms of the integrated area of corrected ECL spectra, with a pulse time of 0.5 s, the intensities of the Ir(III) complexes were between 18 and 102 % that of [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine). However, when the intensities were measured with a typical bialkali photomultiplier tube, the signal of the most effective blue emitter, [Ir(df-ppy)2 (pt-TEG)](+) (df-ppy=2-(2,4-difluorophenyl)pyridine anion, pt-TEG=1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-4-(2-pyridyl)-1,2,3-triazole), was over 1200 % that of the orange-red emitter [Ru(bpy)3 ](2+) . A combined experimental and theoretical investigation of the electrochemical and spectroscopic properties of the Ir(III) complexes indicated that the greater intensity from [Ir(df-ppy)2 (pt-TEG)](+) relative to those of the other Ir(III) complexes resulted from a combination of many factors, rather than being significantly favored in one area.

18.
RSC Adv ; 5: 28582-28596, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26251697

RESUMO

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).

19.
Org Biomol Chem ; 13(22): 6225-41, 2015 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-25958967

RESUMO

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 µg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Norbornanos/farmacologia , Peptidomiméticos , Antibacterianos/síntese química , Antibacterianos/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Norbornanos/síntese química , Norbornanos/química , Relação Estrutura-Atividade
20.
Chem Commun (Camb) ; 51(37): 7827-30, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25853994

RESUMO

Fluorescence microscopy studies using 4-morpholinoscriptaid (4MS) demonstrated rapid cellular uptake of this scriptaid analogue into the cytoplasm but no nuclear penetration. As 4MS and scriptaid have the same in vitro activity against HDACs and KASUMI-1 cells; 4MS exemplifies a rational approach to subtly modify 'profluorogenic' substrates for intracellular studies.


Assuntos
Corantes Fluorescentes/análise , Corantes Fluorescentes/química , Inibidores de Histona Desacetilases/análise , Inibidores de Histona Desacetilases/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Estrutura Molecular , Relação Estrutura-Atividade
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