Plot Issues

1. Play out the sidequests anyway in the back burner

In a way this feels like a Shadowrun situation, and quite frankly if the players are chasing their own (maybe literal) ghosts, the factions are going to hire someone available to do it. Let the party handle their own stuff and a rival party gets the job. You can resolve the quest any way you feel appropriate for where the plot will develop, but now the players need to fight for their reputations. The next player plot hook could be buried in the rival groups.

2. Why not mix it up?

If the party is supposed to be a group of characters with high impact on their world, there is a way to make the character plots intercede with the core plots, even if they happen just a little off kilter from what you need to accomplish like the job is straightforward but Bob's old nemesis just can't see it go well, or George's scorned love demands a favor in exchange for forgiveness, or Nell's long lost sister might be in the mark faction's castle/town/whatever. While they may seem very divergent, the plot device has a setting for looping things together in the strangest of ways such that they all become related and keep the party together.

3. PC the NPC / NPC the PC

Do you have a specific way you want the quests to go? Follow one of the players on their sidequest (and anyone else with reason to be involved) and pre-gen NPCs for the rest of the characters to play - including a core enough personality to keep them involved. Meanwhile, the party does their quest. It might not be the smoothest accomplishment but it would then be up to you as the DM for embellishments but do reward the core party with the quest items for the players performing well in the side arc. This also gives you play room for fuzzy memory parts that you need to ad hoc or retcon.

4. Save this campaign for later

If the players are giving you enough plot to run a full game, it may mean that you should save this campaign for when you have a more attentive party - especially one where you can tell the players what they're in for to make characters in reaction to it. This is my least favorite idea but if they have these in depth characters that run parallel to the world you're running, it may be worth considering.

Motivation Issues

I'm hoping these are not the CN players who just enjoy what I call the Video Game Experience. To me, the Video Game Experience is that to the player, anything in the environment they can interact with needs to be important, monsters are just experience, and the plot itself doesn't necessarily need to matter if they get the levels and the loot. In this case they are almost turning themselves into NPCs if their actions really have nothing to do with the party.
It may be worthwhile to sit down with them to explain that these characters need a few tweaks to make the game harmonic. While a character can be selfish, the fact is that it's hard to run a full party with the truly self indulgent within it. Tell them that they can keep their characters, perhaps even as they are but the player becomes responsible at least up front with why the character is with the group. After encountering a situations where the characters don't mesh or the lone wolf amidst the team, DMs in my area have started telling people that even if they make characters on their own, it's up to them to make party cohesion work. Sometimes it doesn't matter and the DM holds the leash for some major plot hook, but the fact is that in the seemingly sandbox world you have, the party dynamic is player driven.

I think 'the dark wanderer' and MC-Hambone have really good answers, but I wanted to add a few more suggestions. I read up on this specific scenario to get an idea of what the players may have missed, so I'll give my suggestions for how to handle it in this specific situation, and possibly how to use these suggestions more generally. Hopefully at least a little of this will be helpful.

What are the symptoms of the problem the players are trying to solve?

Think of the plot conflict as an illness that the players are trying to diagnose. If they keep thinking that it's Lupus (it's never Lupus), give them another symptom. First things first, when you read through the scenario prior to the session, keep in mind how the main conflict could be effecting the world. The official book should give you a lot of this, but try to think of any "unintended consequences" to serve as a fallback to give clues to the players.

In this situation: the plants along the riverbank could've displayed signs of being poisoned downriver of the poison source, but no signs of poisoning upriver. This way, if the players move past the source, you can just mention that they move into an area where the plants are lush and healthy. Don't specifically say "the vegetation here is not poisoned"...just say that it's beautiful glade, or has green grass, etc.

If they continue to move in the wrong direction, then mention that the most perceptive character notices that the plants there are not poisoned. This should give them a pretty strong clue that they have moved beyond the source of the poison and need to double back. If their samples keep showing up poisoned, then it should tell them that they have a flaw in their methodology.

More generally: regardless of how the conflict began, consider: were there witnesses? Could those witnesses have mentioned it to anyone? Would they seek out help? Would they seek out any of the player characters specifically?

If there were no witnesses, what sort of "footprint" would've been left in the immediate and surrounding areas? ie, did the responsible party have a campfire in the area? Did they leave in a hurry and forget to extinguish it? Maybe this caused a small forest fire that the players could spot, or even smell days after it was extinguished.

What's special about the player's characters?

Within the game world, why is it that these specific people are the ones who can solve this problem? Why can't the town guard, or random civilians, figure it out on their own? What skills/background/items/traits do the players' characters possess which make them uniquely suited to this task?

In this situation: If any of the players' characters hail from the region, they could have a childhood friend who might work in the place where the poisoning began, and would be willing to confide in the player's character. Maybe one of the players has a skill which might help them notice that the poison levels are too regular (if they aren't cleaning out the pot/vial they're using for the samples), such as magience, or a nature skill. This gives you an opportunity to simply say "You notice _____" if the players are going completely off-base.

More generally: At least glance through the players' character sheets beforehand (though ideally you may want to have a copy of each one handy during the game) so you have an idea of what skills/feats they have. If none of the characters has a high enough passive perception (or equivalent) to notice a clue, and the clue itself is vital for game completion, then consider how their unrelated skills might color their perceptions.

For instance, if the players are trying to track down some bandits, and they notice footprints heading north away from the site of an attack, they might just start heading north. If they don't think to actively track the trail (ie, they just say "we go north"), then they won't notice that the bandits turned east after a few miles. You can push them in the right direction by rolling 1d4 and stating that after that many hours, the character with the highest tracking/nature skill (or equivalent) notices that there is no sign of anyone traversing the area. This tells the players that they need to double back and try to find the bandits' trail, but also gives them a realistic little penalty for going off half-cocked.