We'll see how Coyote vs. Acme fairs (and I have not seen The Day the Earth Blew Up, but to my understanding it is pretty much straight-up comedy), but I feel that so far it has always been bit more than awkward trying to fit Looney Tunes into a traditional feature-length three-act narrative, with dramatic stakes. If nothing else, in my eyes all of them have struggled with the fact that it is next to impossible for a story to have both slapstick violence played for laughs, where the consequences of said violence are just shrugged off the next frame, and serious/dramatic violence, where we the audience are meant to be worried about its consequences.
Say, even putting aside the societal-side of "men hurting women is inherently not funny" some people have, in the first Space Jam it is just really weird that after a whole movie of the bad guys physically bashing and hurting the good guys, with all the injuries played for laughs, suddenly one of them trying to hurt Lola and Bugs shoving her away, getting injured in her place, is played as a serious moment. Or, another example, in Space Jam: A New Legacy it is weird to see Bugs falling into a pool of lava being treated as something he needs to be rescued from, when in a typical Looney Tones cartoon the worst that could happen would be the heat of the lava launching him out of the pit, with his bum only slightly singed (although, I guess this could be handwaved with him trying to manipulate Lola).
I think another inherent problem with Looney Tunes/live-action hybrid movies is the fact that it is really hard to mix the tone and energy of the two sides. Charlie Chaplin famously said "How can we compete? These guys don't have to stop to take a breath" in regards to Looney Tunes, so when you shackle the Looney Tunes to a live-action human co-lead, you are limiting their potential. Again, we'll see how the cast of Coyote vs. Acme measure up, but just looking at the movies we have gotten so far, in my eyes you shouldn't go for sport stars, who have limited acting range, or actors like Brendan Fraser (who I know people love, but you gotta admit isn't known for big over-the-top performances), but instead look at someone like Bruce Campbell, Nicolas Cage or Christopher Lloyd.
To give my two cents on the "Space Jam vs. Back in Action" debate, I have to give edge to Back in Action. However, I do not think it is a great movie, more of a "yeah, this is fine when feeling lazy and just wanting to have something on, while having limited options" and I am a fan of Joe Dante. Even then, you can really tell which parts he was actually passionate about and was allowed to make more or less in his way (the scenes featuring only Looney Tunes, without the human cast, some of the "biting-the-hand" meta humor and all the references to old B-movies) and which parts he directed on autopilot, while holding all the studio notes.
And while Brendan Fraser and Jenna Elfman are better actors than Michael Jordan, at least the premise of Space Jam (even though, yes, I do agree with the criticism that the classic Bugs would never need help to take out the Monstars) plays up to his strengths as a performer/athlete, while Fraser and Elfman are just kinda lost in Back in Action. Although, to be fair to them, I imagine that part of the problem was probably with the direction, since Dante is clearly more comfortable with quirky character-actors than traditional Hollywood stars and you know that a version of the movie where he had full creative control wouldn't have cast them.