Mewtwo has less defense than Mew. That’s kinda weird, isn’t it?

No.

What, you want more?

Fine.  What do we know about Mewtwo? He was created in a lab by manipulating Mew’s DNA to create the ‘most powerful Pokémon in the world.’  Now, to me it seems likely that what they were primarily aiming for was pure offensive might, so perhaps they were willing to sacrifice a little of Mew’s resilience (and it’s not a huge sacrifice; Mewtwo’s physical defence is still pretty good) for larger gains in psychic power.  More to the point, Mewtwo’s origin story is essentially a somewhat ham-fisted fable about the dangers of ‘playing god’ with genetics; to me it makes perfect sense that the resulting creation might have some flaws that would not have been apparent in advance.