Reacting to the first set of biological results

19 Jan
Published by pylioja

Subject 

Request for Help

We have received encouraging biological results for the analogues we sent for testing before Christmas. Mat has discussed this here on TSL and on G+. Our best hit came from the "near-neighbour" compound and the original GSK hits came out slightly less active than in their original high throughput screen. However, Paul Willis at MMV rates TCMDC-123794 as a better lead than PMY 14-1 (TSL post). I've already started on the synthesis of the amide (PMY 31) and ether-linked analogues as well as the "linker-less" analogues (PMY 12-5). As mentioned by Paul, it could well be that inherent instability of the ester link would diminish the activity of the compound. We have already found that the free acid and methyl esters themselves are inactive so inclusion of amide or ether linkers could increase activity or at least prolong the metabolic half-life.
Compound targets
The thing that has been holding me up with the amide analogues of TCMDC-123794/123812 is that the reactivity of the parent acid is low with a number of coupling conditions. The best result has so far been achieved using the acid chloride but even this is fairly unreliable. Meredith Jordan here at Sydney has been kind enough to begin modelling this compounds for us using DFT on Gaussian and hopefully this will give us a bit of insight as to why this acid is sluggish to react. Maybe theres a trick we're missing with these coupling?
Couplings
Zoe has been busy making analogues of the near-neighbours. So far we have a reasonable range of aryl analogues and have just started investigating the substituents on the iminothiazolodinone. The next batch of compounds for biology will contain these and, given the high activity of PMY 14-1, we are very excited about how these will perform.
 
We also don't know to what extent the aryl pyrrole core of these compounds affects the antimalarial activity. Currently it could well be that it is the side chain that is more responsible for the activity. How much of the core can we change before we see a drop (or increase) in activity. To this end, I will also submit some derivates of the side-chains for testing for both of the TCMDC-123* series and the "near-neighbours".

Comments

MatTodd's picture

Bill Jackson from Creative Chemistry emailed to suggest you should try at least 1 equiv of HOBt for the DCC amine/amide coupling. Worth a shot...