Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/EDG-MED-10fcb19e
Hi @edgriffen I would be wary substituting with 4-pyrazolyl (Design 5) since this effectively extends the pi system of the isoquinoline and, at very least, would be expected to lead to a reduction in solubility (worse things have happened when pi systems of fused aromatics have been extended). Is pyrazole a substituent on an aromatic carbon in the MedChemica’s ADMET rule database or a replacement for phenyl? I would anticipate less disruption (relative to methylsulfone analogs) to binding modes for Designs 1/2 than Designs 3/4.
I see fluoro as a higher priority than the C7 substituents in Designs 2 and 4 (less likely to disrupt binding mode; no 7-fluoroisoquinolines appear to have been synthesized). The pKa values reported for 6-aminoisoquinoline and 7-aminoisoquinoline (7.2 and 6.2 respectively) suggest that C6 ‘feels’ the pull of the isoquinoline N to a greater extent than C7 and is consequently in less ‘need’ of protection than C7.
Thanks, @pwkenny. The potential fluoro protection at C7 has now been actioned for synthesis, along with attempting to move the sulfone over to that position.
Thanks for letting me know, Matt, and good luck with the synthesis and assays. I would anticipate a greater loss of potency to result from putting methylsulfonyl at C7 than at C6 but still think it would be worth doing.
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