Background Questions about "The Alkyl's"

[sdilones]

Me and @anna-schrecengost are currently looking into the history of the alkyl (specifically with an internal alkyne) and just had a couple of clarifying questions:

1. What exactly makes the side chain a potential metabolic hotspot?
2. Why does adding more than three atoms cause it to lose potency?
3. Why exactly did replacing the the triazole aryl substituent with a cyclo(hetero)aliphatic group lower the potency?
4. The internal alkyne,can only occur because of the benzylic oxidation, and without any substituents on the benzene, the alkyne can't occur, right?

[mattodd]

Hi - you saw #457 , right? The compound you show is not an "alkyl" - it contains an alkyne functional group. I think we need to be careful with terms to avoid confusion. Brief answers to questions:

1. Normally benzylic positions can be hotspots - easier to oxidise. But it depends. I don't know about alkynes as hotspots, but really the alkyne is intended as a useful synthetic precursor to other analogs downstream.
2. No idea. It'd be nice to know. We don't have the biological target, see COMPETITION: A Predictive Model For Series Four #421
3. Don't understand - can you provide MMV or OSM compound numbers or links to relevant structures so that we can see which structures you mean?
4. Ahm, I don't understand your sentence, sorry.

[mattodd]

As per #423 closing this now. Added this issue to DCNYS section of wiki.