Modification of the Triazole Substitution
Attempts at lowering the lipophilicity of the compounds by replacing the triazole aryl substituent with a cyclo(hetero)aliphatic group, linked either by the heteroatom or otherwise (e.g. piperidine, tetrahydropyran, indoline or isoindoline) lowered the potency against PfNF54, as did an aniline substituent. A dimethylpyrazole substituent was also deleterious - note the comparison with MMV670944, which is potent.
One of the original inherited documents for Series 4 indicated that "heteroaryl" was not tolerated in this position, but the data did support this as a blanket conclusion. Pyridinyl was found in 2014 (file mirror) to be a poor substituent, though one inherited compound containing a substituted pyridine was active.
Where an aromatic ring has been used in this position, it appears that a para-OCF3 and -OCHF2 groups generate higher potency than -OCH3 (data from 2014, ELN entry, file mirror)
Sets of (undergraduate-derived) compounds were evaluated in 2015 and 2016 with variation in the phenyl ring attached to the triazole while holding the phenethyl ether pyrazine substituent constant, revealing a high level of dependence of potency on the substitution of the phenyl ring. Thus while a para-chloro substitution pattern (MMV663915) gave rise to high potency, the other isomers and the des-chloro compound (MMV689970) were not potent. Some (low) potency was observed when there was anything other than C-H in the para position; generally substituents in the meta and ortho positions were deleterious.
A selection of benzylic alcohols were synthesised containing different substitution on the triazole ring. Once again, a paraphenyl-OCHF2 group led to potency whereas interestingly, a phenyl substituent led to inactivity, 2-substituted pyridine displayed micromolar activity, again suggesting that substituted pyridines could be further explored. Both cyclic and acyclic aliphatic compounds were inactive.
Generally speaking CN and Cl are well tolerated in the para position of an aromatic ring attached to the triazole, leading to highly potent compounds.
Replacement of the phenyl ring with a bioisosteric para-substituted cubane (for improving the solubility) is not well tolerated
