Uhhm....I think 'challenging' is a word you can interpret in many ways.
It depends on your skills and preferences.
But for me, I think I can say

All of them

Are challenging. In their own way.
In RE3, for example, it is the fact you can't run and shoot.
RE4 has Ashley. Enough said, folks xD
RE5 and RE6...yeah...there it is the inventory. I don't know, bur why ? XD
Soo I think it really depends on who you are and many other factors :)

Which was the most challenging for you ? :)
Tell me in the comments :D

See ya \(^o^)/