Crises across West Asia dominated the first day of the annual UN summit, where Western
leaders sought to increase pressure on Damascus and Iran to abandon confrontation and seek negotiated settlements.
And Obama went further, declaring: "The regime of Bashar al-Assad must come to an end so the suffering of the Syrian people can stop, and a new dawn can begin."
Obama was unequivocal on Iran, which is locked in a stand-off with the West over a nuclear programme that Washington alleges is designed to produce a weapon that could tip the balance of power in an already volatile region.
"Make no mistake. A nuclear-armed Iran is not a challenge that can be contained. It would threaten the elimination of Israel, the security of Gulf nations, and the stability of the global economy," Obama said.
"That is why a coalition of countries is holding the Iranian government accountable. And that is why the US will do what we must to prevent Iran from obtaining a nuclear weapon," he declared.
Six weeks before he is due to seek re-election, Obama is under pressure on the foreign policy front, with criticism of his handling of the killing of US diplomats and claims he is not standing closely enough behind Israel.
He invoked the words of Mahatma Gandhi as he remembered the US envoy, saying: "It is time to heed the words of Gandhi: 'Intolerance is itself a form of violence and an obstacle to the growth of a true democratic spirit'."
His speech was designed to counter claims from rival Mitt Romney and also to renew his outreach to the Muslim world after two weeks of anti-American violence triggered by a movie trailer that insulted Islam.
Obama said the Arab Spring would lead to improved democracy and living standards in a Middle East but, while he condemned the film, he insisted no insults could justify violence.
