The general died of wounds suffered in fighting at Mleiha, a key battleground southeast of the capital, making him one of the few top-ranking officers whose deaths have been announced during Syria's three-year war.
The air defence forces' headquarters is in Mleiha, a key flashpoint in current fighting around Damascus.
Because the rebels do not have an air force, the forces under Isaac's command have rarely been deployed for air defence.
"The regime's air defence force is to face a possible US attack, but in this war it is using its firepower against the rebels," said Syrian Observatory for Human Rights director Rami Abdel Rahman.
The army's entire arsenal and forces are deployed in Damascus's war against rebels seeking to overthrow President Bashar al-Assad, whose regime brands the uprising as a foreign-backed "terrorist" plot.
Abdel Rahman called Isaac's death an "important psychological blow" to the regime.
For more than a month, the army backed by Lebanese Shiite Hezbollah has been battling to recapture Mleiha, a strategic rebel bastion.
It has been under siege for more than a year, and under near-constant bombardment for more than a month.
The Observatory said that despite initial regime advances in Mleiha, the rebels have recovered ground, retaking several buildings around the central town hall.
While the army is squarely in control of Damascus, rebels still hold a number of towns and villages on the outskirts, despite a suffocating blockade and frequent air strikes and shelling.
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