Ideas for a Hypothetical Tobey-Man 4:

 Spider-Man 3 ended with a dead Harry, Sandman escaping and Pete getting together with MJ. There are rumors of a possibility of getting a 4th Tobey movie. Here's the top Ideas to what I'd like to see.

Spectacular Spider-Girl:

Peter and MJ got married and became parents to a Teenage girl who began developing Spider-Powers. Now as a 40-something Spider-Man must navigate the Responsibilities of being a parent of a teenage Superhero.

Or

Miles Morales:

There's a new Spider-Man in town and he's inexperienced. It's up to the original Spider-Man to teach him that with great power comes great responsibility.

The theme is passing the torch,  because Tobey is getting too old to reprise the role for too much.

So, the idea is to set up Peter as a mentor to a new Spider.

Now who could we have as Villains for this movie? I'll separate the lists between characters that could work for May, Miles, or both.

Not all villains should be used in the same movie.

May villains:

Kaine: 

Unlike the comic book version, This Kaine is NOT a clone of Peter Parker, but a man (Preferably Andrew Garfield) who was injected with the Venom of a newer model of the Super Spiders that created Spider-Man in addition to Goblin Formula by Oscorp scientist Miles Warren (bonus points if Warren is played by Christopher Barnes)

Hobgoblin:

Essentially, Roderick Kingsley (Neil Patrick Harris) became the majority shareholder Oscorp. Throughout the years, he had funded various minor criminals like Shocker, Boomerang, Chameleon, Big Wheel, Prowler, etc. After seemingly dying ina fight with Spider-Man (where Peter is forced to hang the webs) with the new Spider-Girl, the Hobgoblin returns.

Lady Octopus:

Here we will have to depart from the comics a bit. Carolyn Trainer would be related to Doc Ock's wife Rosie and was a teenager whenAunt  Rosie and Uncle Otto died because of Spider-Man. Recreating and improving on Otto's Tentacles, Carolyn wants to destroy everything related to Spider-Man including the new Spider-Girl.

Chasm:

A genetically engineered copy of Peter Parker (Tobey Maguire, Digitally de-aged) made from Peter's DNA merged with the Symbiote. Driven crazy from the memetic memories of Peter, the symbiote, and their current host, Chasm is looking to destroy Peter Parker and his legacy.

Miles Villains:

Hydroman:

Morris Bench was a criminal who was part of a gang that ended up shooting officer Jefferson Davis. He escaped police by jumping down a pier and being dragged by currents to his death. When he woke up, he was human water.

Prowler:

Aaron Davis was the best there is at what he does... Burglary, Coorporate Espionage, Assassination. Tasked to Kill Spider-Man, Aaron is on the hunt of his own nephew.

Scorpion:

The appearance of a second Spider-Man pushed Jonah over the deep end and sponsored Oscorp's new exo suit specifically designed to deal with super powered threats like Spider-Man.

Could fit for both:

Morlun:

Fuck you that's why. Essentially, a side effect of the Universe hopping shenanigans brought by Tom Holland's Spidey. It awakened a monstrous entity designed to hunt down meddlers who interfered with otjer universes. MORLUN was specifically designed to kill spiders.