https://nova.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47111 Wed 14 Dec 2022 10:19:31 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48769 Wed 05 Apr 2023 14:02:39 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48768 Wed 05 Apr 2023 13:55:29 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:50596 Tue 08 Aug 2023 11:56:57 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38461 50=30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.]]> Thu 18 Nov 2021 10:32:22 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:8246 Sat 24 Mar 2018 08:40:38 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:5130 Sat 24 Mar 2018 07:48:56 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47778 Mon 30 Jan 2023 10:09:52 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:44889 N′,2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL⁻¹. Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 μg mL⁻¹. Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16–64 μg mL⁻¹ active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL⁻¹. A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16–64 μg mL⁻¹. In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 μg mL−1 to inactive (MIC>128 μg mL⁻¹) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 μg mL⁻¹ against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 μg mL⁻¹ with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains.]]> Mon 24 Oct 2022 14:46:25 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53783 Mon 15 Jan 2024 10:24:12 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:41065 50 values of 0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 times more potent in MDA-MB-468 cells than normal MCF10A breast cells (GI₅₀ of 0.098 vs 5.4 μM) and more than 130 times more potent than in cell lines derived from pancreas, brain and prostate (GI₅₀ of 0.098 vs 10–13 μM). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N-phenyl moiety for biological activity.]]> Mon 08 Aug 2022 15:04:26 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:50565 Fri 28 Jul 2023 11:27:49 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42606 Fri 26 Aug 2022 15:48:48 AEST ]]>