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22 March 2015 - 5:18pm
Commenting on: Ideas on disappearing furan in TFA?
Furans are susceptible to strong acid-catalyzed hydrolysis to ring-opened products. The loss of furan-associated methyl and aromatic peaks is consistent with this. The doubling of the original CH peak and lack of additional methyls from the ring opened furan to a probable diketone species suggests that this fragment of the molecule somehow detached from the amide, giving the doublet coupling between the CH and NH peaks (NH at ~8.5 ppm). Additionally, if the t-butyl signal ascribed to t-butyl trifluoroacetate integrates to 9 (it appears to but I can't tell) theres the possibility that the tert butyl cation formed during the reaction attached to some other portion of your molecule before it was scavenged. Since your furan is very electron-rich with the 2 alkyl substituents strong acids will be a difficult process to optimize. I would suggest the following: 1. Trying weaker acids such as formic acid for longer reaction times. 2. Trying thermolysis conditions (silica gel and microwave heating, quinoline solvent, heat to 200°C or more, etc.) 3. Adding cation scavengers (thioanisole, phenol, etc.) to reaction mixtures to prevent t-butyl migration. Note I took some of this information from Greene's Protective Groups in Organic Synthesis, 4th edition. I personally am working on t-butyl esters but some of the conditions also remove Boc groups and have been applied to furan-containing molecules. Good luck!
anacardic compounds to cure TB
5 March 2014 - 12:27am
Commenting on: Tuberculosis Research Community
Anacardic compounds in cashew pears and raw cashew nuts are very lethal to gram positive bacteria. Therefore it is possible that they would prove useful against tuberculosis since tuberculosis is said to be related to gram positive bacteria. You may see a discussion of their successful use against tooth abscess bacteria in http://charles_w.tripod.com/tooth.html . Perhaps you could use your influence to get what would be an easy, safe experiment performed using cashew nuts, cashew pears, or mango fruit. Anacardic acids could even possibly be used to see if they add to the potency of other medicines.
Isonicotinoylhydrazones were synthesized from a natural product anacardic acid, a major constituent of cashew nut shell liquid. The unsaturated side chain in anacardic acid and its 5-nitro derivative were converted into C8′-aldehydes by oxidative cleavage. C8′-aldehydes are then coupled with isoniazid (an anti-TB drug) to obtain N-isonicotinoyl-N′-8-[(2′-carbohydroxy-3′-hydroxy) phenyl] octanal hydrazone (5) and N-isonicotinoyl-N′-8-[(2′-carbohydroxy-3′-hydroxy-6-nitro) phenyl] octanal hydrazone (6). These isonicotinoylhydrazones of anacardic aldehydes showed potent antimycobacterial activity against Mycobacterium smegmatis mc2155. The synergistic studies of 5 and 6 with isoniazid showed more inhibitory activities than isoniazid alone. Compounds 5 and 6 also showed activity against Mycobacterium tuberculosis H37Rv. (abstract from http://www.sciencedirect.com/science/article/pii/S0223523406003278 )
Sincerely, Charles Weber
24 September 2013 - 8:20pm
Commenting on: Development of Novel Antitubercular Drugs
There is apparently protein available from MCSG
- Source Organism
- Mycobacterium tuberculosis H37Rv
- Target Name
- ndh gene product [Mycobacterium tuberculosis H37Rv]
- Target Category
- biomedical,disease,individual organism,PSI Biology partnership
- Target Rationale
- We identified an inhibitor active on whole cells that appears to target this protein.
- Site ID
- Lab List
- Last Update
- Project List
- Database References
- MCSG: APC105972, GenBank: 15608991
Hi there, just watched Tom's
17 May 2013 - 11:32am
Commenting on: Sulfonamides
Hi there, just watched Tom's Google Tech Talk and thought I'd have look around.
I worked on a project that used sulfonamides and we found the tetrazole was a good bioisostere. It may reduce the solubility as you'd have 3 aromatics in conjugation but it's a option if you want some variety or to explore how the sulfonamide contributes to binding.
Meeting Recording and Minutes
21 March 2013 - 2:57am
Commenting on: OSDDMalaria Agenda, Feb 26th 2013
Minutes and Discussion: http://www.thesynapticleap.org/node/441
SOLVED-onamides - perhaps!
28 February 2013 - 5:44pm
Commenting on: Sulfonamides
As per my tweet/lab book here, it looks like I've got these to chlorinate cleanly with oxalyl chloride - so I should ask, do we want both compounds you've shown here? E.g. the ones based on glycine (NH) and sarcosine (NMe). I can make both here relatively easily, as I have a bit more of the sulfonic acid lying around.
25 February 2013 - 12:42am
Commenting on: API Form & Drug product research
If a DKR version of this process could be developed (or even using it as it is) there would be no waste in producing (R)-Praziquantel.
SAR refresh comment
12 February 2013 - 1:23pm
Sounds fine but would still suggest in the gentlest possible way that it's imprudent to assume 1) or b) untill you accumulate a substancial collated data set that defines this variance statistically. The pharmacophore work is also dependant on this as you know.
SAR refresh - good idea
9 February 2013 - 9:33pm
Sure - I'm in Sydney this week. I'll get together with the local team and get this posted. I think the % inhibition figures are mostly for low-actives, though I do think we are waiting on a very early set of numbers from the Ralph group if memory serves. We're expecting biological data for the latest set of compounds in a week or so from Vicky's group, and that may inform our discussion, so we should wait till then - if the latest compounds (near neighbour thiazolidinone set) are good-looking (since we've made them more soluble) then they become of greater interest. Let'd revisit when we know. I'm not too concerned about resubmitting IC50s, but it's something we could do if there's a consensus that this is necessary. The reasons are: 1) early figures for the first round carried out by several labs were quite consistent, meaning spatial variance (another form of temporal variance..) is low, and b) the labs doing the evaluation have these assays running all the time, meaning there is unlikely to be a lot of variability in set-up. And degradation of compounds over time could presumbly be assessed by NMR. But very happy to vote on it.
8 February 2013 - 1:06pm
Inspired by being featured with the gang in Chemistry World and PubChem pushing towards 50 mill, I would like to catch up with any searching you might think useful. Can I request an SAR update/refresh of say the "top ten" ? Just a simple table would do of SMILES, InChIKey and IC50s. If you have any outstanding "% inhbition" figures I'd suggest getting IC50s done so they are comparable. I'd also suggest re-submiting at least your top-five for IC50s, so that time-separated duplicates will provide some idea of variance.
6 January 2013 - 3:18pm
The use of sulfur trioxide pyridine is looking promising. I was wondering have you considered forming the sulfonamoyl chloride and treating this with the pyrrole? Maybe using pyridine or 4-DMAP as a nucleophilic catalyst?
So what’s going wrong?
3 January 2013 - 10:31pm
Commenting on: Williamson's attempted ether synthesis
I am no pyrrole expert, but I was wondering could your alcohol and other alkylated products be decomposing along these lines?
3 January 2013 - 12:31am
3 January 2013 - 12:30am
3 January 2013 - 12:26am
Context of late stage gametocyte assay to whole project
15 December 2012 - 2:21am
Commenting on: Late Stage Gametocyte Assay for Arylpyrroles
To see the relevance of this assay to the overall results for the arylpyrroles, see the Story So Far summary. The data provide a clear delineator between original GSK arylpyrroles and the near neighbour set (the iminothiazolidinones).
Update on the near neighbour thread...
15 December 2012 - 1:44am
Commenting on: Known Near Neighbours of Initial Tres Cantos Leads
The near neighbours were to some extent included in the project, though not all of the structures included above have, to date, been included. See the overall Story so Far for the current situation. Some of these near neighbours were very insoluble, though they did show significant late stage gametocyte activity. The compounds remain of interest.
Yes - triazole is a simple target
13 December 2012 - 10:05pm
That's right - it's a "well, why not" shot. The S/Ms are simple and the chemistry should be fine. Would be great if you wanted to take a pop at it. See my comment below about the lab book though - important to share the data.
Note that anything you make in the UK can be screened for activity there/in Europe vs. controls - no need to mail to Aus...
13 December 2012 - 10:03pm
That'd be great. Happy to use the online lab notebook to record your data? Even repeats of reactions are useful, but certainly when you get to new/trial things. You could use Matin's, or start your own. Any of the team can help with that. The chlorosulfation seems to be going, but since we don't isolate the intermediate, or at least characterise it properly, it's not clear what's going wrong.
13 December 2012 - 12:02pm
I've dropped Matin a comment as the sulfonamides look interesting: We're playing with chlorosulfonation here in Edinburgh. Given that I'm about 12,000 miles away I'll just make some of the fluoroaryl-pyrrole SM myself this weekend.