Perhaps a secret organization that had been hidden for centuries and didn't want the new order that Konoha represented. They could have dark magic or forbidden jutsu at their disposal and use it to try and stop the First Hokage from achieving his goals. This would force the First Hokage to not only rely on his physical strength and known ninja techniques but also to find ways to counter the unknown and mysterious powers of this secret organization.
A group of corrupt politicians within the village itself could be the main antagonists. They might be secretly plotting to undermine Naruto's authority as the 5th Hokage in order to gain more power for themselves. They could be making deals with other villages or ninja groups that are not in the best interest of Konoha, and Naruto has to expose and stop their schemes.
It could be some of the old enemies who were thought to be defeated but managed to come back. For example, Orochimaru's former followers who still hold a grudge against Naruto and Konoha. They might see Naruto's retirement as an opportunity to strike.
It could be some rogue ninjas who were against the peace treaties after the war. They might form a group and try to disrupt the newly - established peace in the ninja world.
Perhaps a powerful and corrupt merchant group could be the antagonists. They are secretly trying to take over the village's economy and resources. They use bribes and blackmail to get their way. The Sixth Hokage discovers their plot and has to stop them without causing too much chaos in the village's economic system. They may also have some ninja mercenaries working for them.
Another interesting plot would be to imagine if the First Hokage had to face a threat from within the village during its early days. This could be a group with different ideals who wanted to take over or change the way Konoha was being built. It would show his leadership skills not only in battle against external enemies but also in dealing with internal politics and unrest.
The remnants of an old enemy clan that the Nidaime Hokage had defeated could be antagonists. They might be seeking revenge for their past losses.
One possible main antagonist could be a shinobi from another village who fears Sakura's potential as Hokage. This shinobi might try to undermine her by causing chaos in her village or spreading false rumors about her abilities. Another could be someone within her own village who has a long - standing grudge against her or her family and doesn't want to see her in a position of power.
Obviously, the First Hokage himself is a central character. His brother Tobirama could also play a major role, as they were closely associated. Madara Uchiha would be a great addition too, considering their complex relationship in the Naruto lore.
The Sound Ninjas could be great antagonists. They could use their own unique parkour - like skills to try and stop Naruto. They might be chasing him through the forest, and Naruto has to use his parkour skills to outmaneuver them.
Maybe some corrupt officials within the prison system itself. They oppose Naruto's more humane and reform - focused approach to prison management. They might try to undermine him at every turn, for example, by cutting off resources or spreading false rumors about him among the prisoners.