Compounds sent for testing in Dundee, December 2017

[david1597]

The final batch of compounds for 2017 have been shipped to Dundee for testing, including:

• a caged compound (OpenSourceMalaria/OSM_To_Do_List#510)

• the Pfizer biosynthesis compound (OpenSourceMalaria/OSM_To_Do_List#525), and an H-bond donor analogue

• late stage functionalisation compounds

• Suzuki coupling compounds

[mcoster]

Nice work @david1597 - I particularly like the late-stage functionalisation compounds. We recently ordered a bunch of the sulfinate reagents in for a different project, and I was going to get someone to try that chemistry on some OSM compounds - looks like you've already gone down that path and it works! :) Out of interest, did you see any products of reaction at other positions?

[david1597]

Yep we're keen to see how these all turn out, @mcoster. All those late stage functionalisation compounds were the work of @ConorGraham in his Honours project over the last year. He didn't see any products from reaction at the other positions. It's interesting yep! That sulfonamide above is from @maratsydney series. I'm also considering installing it in place of the phenol in the Pfizer biosynthesis compound.

[mattodd]

Yes, sorry about the work from @ConorGraham not being public domain yet - the application of methods to OSM compounds evolved during the year from what is otherwise a closed project. He's just finishing up Hons, but then we'll get all the relevant lab book entries public domain and summarise some things.

[mcoster]

@david1597 - a sulfonamide in place of the phenol in the biosynthesis series sounds like a great idea. If it's successful, you can also easily acylate sulfonamides and the product N-acylsulfonamides would be also be an interesting bioisostere.

[david1597]

EDIT: This comment contains incorrect data. A couple of the compounds have the wrong MMV number written below them, and the data from the two runs is incorrect in some instances. I'm leaving this comment with the incorrect figure so that the comments from others immediately below make sense and correspond to something. Scroll down to the Jan 11th 2018 comment from myself for the correct data

Results are in. There are a couple of issues... 1) The potency of the synthesised 'Pfizer phenol' is not as expected. The results from the biosynthesis had indicated this to be single digit nM, we've got a result of over 4 uM here. This needs to be investigated asap when I return in January, starting with checking the spectra against that obtained from the biosynthesis (we need to obtain these first). Obviously, this is is the basis of many of our current efforts. 2) Some of the repeated runs aren't in agreement. Both values are shown in these cases, and with a *. Will investigate this too when everyone returns.

Merry Christmas everyone! Here's to a happy, healthy, and successful 2018!

[MFernflower]

the fact that MMV1577581 comes back as mildly potent makes we wonder if we should consider making and screening the acetoxy and methoxy derivatives of this compound?

[drc007]

Hi,

There are two structures numbered

MMV1577581

One on top row, the other on the bottom.

Chris

On 23 Dec 2017, at 08:27, David Smith notifications@github.com wrote:

Results are in. There are a couple of issues... 1) The potency of the synthesised 'Pfizer phenol' is not as expected. The results from the biosynthesis had indicated this to be single digit nM, we've got a result of over 4 uM here. This needs to be investigated asap when I return in January, starting with checking the spectra against that obtained from the biosynthesis (we need to obtain these first). Obviously, this is is the basis of many of our current efforts. 2) Some of the repeated runs aren't in agreement. Both values are shown in these cases, and with a *. Will investigate this too when everyone returns.

Merry Christmas everyone! Here's to a happy, healthy, and successful 2018!

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[edwintse]

@drc007 Thanks for pointing that out. The top row compound has the correct MMV number. The bottom row compound should be MMV1577580

[edwintse]

@MFernflower The methoxy derivative has been tested before (MMV688897) and is inactive at >10 uM. Not sure the acetoxy is worth pursuing though.

[drc007]

I’m not sure how stable the acetoxy would be, very susceptible to hydrolysis.

On 24 Dec 2017, at 07:14, Edwin Tse notifications@github.com wrote:

@MFernflower https://github.com/mfernflower The methoxy derivative has been tested before (MMV688897) and is inactive at >10 uM. Not sure the acetoxy is worth pursuing though.

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[MFernflower]

Would it be possible to couple MMV1577580 to some N,N-Dimethylsulfamoyl chloride ? sulfamates show interesting hydrogen bonding properties (mainly receptors but weak donors - also extremely flexible molecules) @edwintse / @mattodd / @david1597 update 12/26/17: sulfamates are also pretty much impervious to CYP enzymes - case in point being topamax's 20 hour half life!!!!

"even though it's the holidays I can't help thinking about it" - It's totally fine, I think about chemistry everyday

Edit: it seems like the hydroxy compound is useless - please disregard my idea

[mattodd]

Merry Christmas everyone. Just on MMV1557865 (even though it's the holidays I can't help thinking about it) - the disconnect between the compound arising from the Pfizer work and the chemical resynthesis is the top priority for early Jan, when we resume. It's too early to abandon this since we need to check what we had in both cases, meaning we need to compare the NMR spectra and any other data to confirm identities. Along that general line I like the look of MMV1577574, with the H-bond donor in the same general position, but one Ar ring fewer.

[edwintse]

UPDATE: Hi everyone, it appears that there's been a mix up with a few of the MMV numbers and associated potency data. (You'll notice that there are two MMV1577574's. The first should in fact be MMV1577573.) As a result the potency data for 573 to 581 are not for the respective compounds. The remaining compounds are ok. Everything should be resolved in early January. We'll post again when everything is fixed.

[cdsouthan]

To err is human and no probs of course. But JFTR did you prepare the shipment on your own rather than arranging for two of you to cross-check each other?

[edwintse]

Previously I have done the shipments but for this last batch I was already away on holiday with limited internet access so David organised the shipping. The registration of the compounds was fine. There was just a mix up with the spreadsheet that was sent to Dundee. We will cross-check for future shipments.

[david1597]

Corrected potency results for the first run of these compounds is here:

[MFernflower]

Is it possible that some of the Pfizer phenol compound oxidized to the carboxylic acid - thus explaining the differences in potency between runs? @david1597 @mattodd

[david1597]

The second run of data has finally come through from the December shipment. Averaged potencies are indicated below.

• it was a largely non-potent selection
• OSM-S-412, the 'Pfizer phenol' is confirmed multimicromolar potency, although we now know this was not the potent compound originally made in that biosynthesis.
• one of Ed's cages, OSM-S-433 is on the threshold of sub micromolar potency
• the solitary potent hit OSM-S-369 from this batch was a repeat synthesis. This batch gave a value of 301 nM compared to the previous value of 251 nM.

The data have:

• been entered into the Master Chemical List
• uploaded to the 'Not yet Incorporated' section of the wiki
• uploaded to my ELN, along with the raw data curves

There are still some remaining action points:

• revision of OSM-S-328 structure in ScienceCloud. The structure shown here is the corrected revised structure.
• correction of OSM-S-412 data as it still has the original Pfizer potencies associated with this number. We now know that these results correspond to a different structure.
• revise/correct structure of OSM-S-509

Edited remaining action points

[david1597]

The first and third bullet points in the previous post have been addressed. For completeness, here are the final potency results with corrected structures for this batch along with a table of individual values. The Pfizer phenol (OSM-S-412) point still needs to be addressed and I need a little help from the MMV data specialist to edit this. Once done this issue will be closed.

MMV number	OSM number	Internal number	Potency 1	Potency 2	Potency 3	Potency 4		Average
MMV1577580	OSM-S-328	EGT 292-1 (f11)	>10	>10
MMV897698	OSM-S-369	EGT 92-1/CG 81-1	0.248	0.354				0.301
MMV1557865	OSM-S-412
MMV1577573	OSM-S-433	EGT 286-1	1.297	0.859				1.078
MMV1577581	OSM-S-442	EGT 295-1	3.872	2.197				3.0345
MMV1577574	OSM-S-497	EGT 281-2	>10	>10
MMV1577575	OSM-S-498	EGT 282-1	>10	>10
MMV1577576	OSM-S-499	EGT 283-1	>10	>10
MMV1577577	OSM-S-500	EGT 284-2	>10	>10
MMV1577578	OSM-S-501	EGT 290-1	>10	>10
MMV1577579	OSM-S-502	EGT 292-1 (f1-8)	7.95	4.282	>10	1.191	8.723	5.5365
MMV1577514	OSM-S-503	CG74-1	>10	>10
MMV1577566	OSM-S-504	CG82-5	>10	>10
MMV1577567	OSM-S-505	CG86-1	>10	>10
MMV1577569	OSM-S-506	MK029-1	>10	>10
MMV1577570	OSM-S-507	MK019-1	>10	>10
MMV1577571	OSM-S-508	MK028-1	>10	>10
MMV1577572	OSM-S-509	MK023-1	>10	>10
MMV1577568	OSM-S-510	MK027-1	>10	>10