Advice Needed: Generation of Analogues in the Thienopyrimidine Series

10 Dec
Published by JimCronshaw

Seasons greetings all. This is the December 2012 update from my side of the Todd lab. I have finished my honours project and submitted my thesis to obtain Hons I - which is highly pleasing - and I'm back for a period of time to assist the Todd group and their antimalarial project. Specifically, I hope to generate a variety of analogues of the hit compound within the aminothienopyrimidine series (Figure 1)


Figure 1: The Hit Compound in the Amintothienopyrimidine Series

Firstly, my hons thesis is publicly available from FigShare. It contains a very thorough review of this project, and together with "the story so far" one can find a comprehensive review of the Todd group's open source antimalarial drug discovery project.

Previously, I had reported difficulty in getting a Suzuki reaction to work, and this problem formed the focus of my last TSL post. At this stage it appears as if I have got this Suzuki reaction to work by employing the conditions that I had used to generate the boronate esters that I had been using (Scheme 1). It is slightly upsetting that I had used these conditions earlier on in the year but had lost the products somewhere (despite re-extracting the aqueous layer and celite filter). Oh well...

Scheme 1: Successful Suzuki Methodology

The generation of a host of analogues is now desired so that we can obtain a structure-activity relationship for the series. The question is, what analogues ought to be generated? I already have a few chemicals readily available in house which can be used in this investigation. A thienopyrimidine scaffold bearing a morpholine group at the 4-position is available. Hopefully, a thienopyrimidine scaffold bearing a CF3 group at the 2-position will be ready shortly. In addition, both m- and p- substituted boronate esters are readily available. (Figure 2).

Figure 2: Readily Available Suzuki Reaction Coupling Partners

I'd like input as to what other compounds ought to be synthesised though. A few clues are available from the testing that has already been undertaken by the Avery group at Griffith University. A few very simple analogues were tested for antimalarial activity, none of which displayed fantastic potency. The only compound that did appear potent also led to haemolysis in the whole cell assay (Figure 3). The clearest conclusion - which is admittedly premature - is that the thienopyrimidine scaffold on its own is insufficient to generate antimalarial activity. Some kind of substitution is necessary. If the aminothienopyrimidine hit compound is proven to be active, then substitution at the 6-position will be judged as necessary.

Figure 3: Biological Results for the Thienopyrimidines Synthesised In-House

Commercially available analogues of the aminothienopyrimidine hit compound were obtained and also tested for antimalarial activity. Again, none of them displayed fantastic activity, though a few were active (Figure 4).

Figure 4: Biological Results for Commercially Sourced Compounds

The active compounds were limited to those bearing a methoxybenzene substituent at the 6-position. These data back up the idea that subtitution at the 6-position is necessary for antimalarial activity.

Finally, a search for any compounds bearing a thienopyrimidine moiety within the ~13,500 compounds that GSK identified as hits (hdoi:10.1038/nature09107) was performed on the chembl database. Sadly, the complete dataset is unable to be stored on the chembl website, and thus, a selection of the more promising compounds found on that list are found below:


To arrive at these results, use the structure search tool available at this link. One can search for whichever compounds they desire, but the results I have arrived at were based on the substructure search for the following molecule:

SMILES: O=S(C1=CC=CC(C2=CC3=C(C(N)=NC=N3)S2)=C1)(N)=O

Some trends can be identified in these data. The trend of activity depending of the presence of aryl substitution at the 6-position is noted. The presence of substitution on the amine present at the 4-position looks as if it can be varied widely, though the absense of substitution on this amine gives the best results in these data. Alice Williamson noticed that compounds with an absense of aryl substitution at the 6-position seem only to be active when subtituted at the 2- and 4-positions. Some of the more active compounds have very high LogP values, though presumably this could be improved by substitution of heteroaromatic and heteroaliphatic rings for their less polar counterparts.

At this stage it's harder to generate any more specific conclusions with my limited experience in medicinal chemistry. The advice of those more experienced in this art would be appreciated. Advice of this sort would allow us to prioritise which analogues of the thienopyrimidine hit compound ought to be generated. Analogues produced through this advice would allow us to generate a structure-activity relationship for this compound, as required for compounds at the early lead development stage according to the MMV compound progression criteria.


MatTodd's picture

Well, one of the nice things here is that you've already done the commercial assessment, so we're left with what can we make and what can we otherwise acquire?


Synthesis is governed by how much time you have - I think you want to try all permutations of the coupling partners you have to hand, plus phenylboronic acid as a control. Wasn't there a urea you were looking at? Other boronates in the building?


Then can you try a SciFinder (etc) search for analogs that are not commercial, so see if anyone is making compounds like this? Perhaps you've done this recently?

This is a good collation but I suggest you consolidate the SAR in more scope and detail before investing in major analoging efforts.  In particular  you need the assay data nailed down as best as possible.  You at least should have the IC50s repeated across these series, ideally as a single  batch, with technical error determinations by replicates and internal controls.  Note at the moment you can't compare the apples of  % inhbition at fixed conc. with the pears of  IC50 curves that probably have different shapes.