The coalition has been hitting IS in Syria and Iraq since mid-2014 but has also been involved in recent confrontations with President Bashar al-Assad's forces, raising fears of the United States being drawn into Syria's civil war.
The White House yesterday accused Assad's regime of preparing a potential chemical attack and warned it would pay a "heavy price", but Defence Secretary Jim Mattis said Washington was determined to keep a strict focus on fighting IS.
Observatory chief Rami Abdel Rahman told AFP the strikes killed 42 prisoners and 15 jihadists in Mayadeen, a large town in the eastern province of Deir Ezzor.
Most of Deir Ezzor province is controlled by the jihadists and it has been the target of air strikes by both the coalition and the Syrian army and its Russian ally.
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The US-led coalition said last week that it had killed IS's top cleric Turki Binali in a May 31 strike on Mayadeen.
US-backed forces are pushing to oust them from their last major urban strongholds, Raqa in Syria and Mosul in Iraq.
But Washington's involvement in Syria has also become increasingly complex.
Yesterday, the White House said preparations were underway by the regime for a chemical weapons attack, similar to those undertaken ahead of an apparent chemical attack on a rebel-held town in April.
"The United States is in Syria to eliminate the Islamic State of Iraq and Syria," White House spokesman Sean Spicer said in a statement.
April's attack on the rebel-held town of Khan Sheikhun was reported to have killed at least 87 people, including many children, and images of the dead and of suffering victims provoked global outrage.
The regime denied any use of chemical weapons.
Washington launched a retaliatory cruise missile strike days later against a Syrian airbase from where it said the chemical attack was launched, the first direct US action against the Syrian regime.
Yesterday's White House statement drew condemnation from Moscow, a key Assad ally, with Kremlin spokesman Dmitry Peskov telling journalists: "We consider such threats against the Syrian leadership to be unacceptable."
US forces will not fire on targets "unless they are the enemy, unless they are ISIS," he said, using another acronym for IS.
"We just refuse to get drawn into a fight there in the Syria civil war, we try to end that one through diplomatic engagement."
Coalition forces on the ground have accused pro-regime fighters of targeting them in recent weeks, as they shot down two Iran-made attack drones and a Syrian fighter jet.
So-called "deconfliction" hotlines are used regularly by the two sides to notify each other where they are operating and avoid accidents.
Such hotlines will only grow in importance if the coalition pursues IS fighters into the Euphrates Valley following their assumed defeat in Raqa, as pro-regime forces also move toward the same region.
"You've got to really play this thing very carefully," Mattis said. "The closer we get, the more complex it gets."
Syria's war began in March 2011 with anti-government protests and after a regime crackdown evolved into a complicated, multi-front war that has killed more than 320,000 people and forced millions from their homes.
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