Defending champion, Novak Djokovic suffered a shock defeat by world number 117 Denis Istomin in the second round of the Australian Open.

The six-time winner struggled for rhythm and lost 7-6 (10-8) 5-7 2-6 7-6 (7-5) 6-4 in four hours and 48 minutes.

It was the first time Djokovic, 29, ha lost in the second round of a Grand Slam since 2008 at Wimbledon.

The result leaves world number one Andy Murray as favourite to win his first Australian Open title in Melbourne.

It was only the second time in seven years that Djokovic has lost to a player ranked outside the top 100 – his defeat by Juan Martin del Potro, ranked 145th, at the Rio Olympics in 2016 being the other occasion.

Meanwhile, Six-time champion, Serena Williams and former winner Rafael Nadal both reached the Australian Open third round with straight-sets victories on Thursday.

Williams, 35, who is attempting to win an Open era record 23rd Grand Slam singles title, beat world number 61 Lucie Safarova 6-3 6-4 in Melbourne.

“I’m really happy to have got through that,” said the American second seed.

Nadal, who won the tournament in 2009, eased through 6-3 6-1 6-3 against 2006 finalist Marcos Baghdatis.

Williams beat 29-year-old Czech Safarova in the French Open final in 2015, and needed one hour and 25 minutes to see off the former top-10 player on Thursday.

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“It’s never easy having to play in a second round against someone you have seen in a final,” she added. “I’ve played two former top-10 opponents, but it’s a great way to start the tournament.”

Williams lost the Australian Open final last year to Angelique Kerber, but went on to win at Wimbledon and equal Steffi Graf’s Open era record of 22 Grand Slam singles titles.

She will continue her bid for the record against 23-year-old Nicole Gibbs, who beat fellow American Irina Falconi 6-4 6-1.

Fourteen-time Grand Slam winner Nadal will face promising teenagerAlexander Zverev in the next round after the German beat 18-year-old American Frances Tiafoe 6-2 6-3 6-4.

Nadal, 30, says the 19-year-old world number 24 “can be a future world number one”.

“It will be a big challenge for me,” said Nadal. “He is a potential Grand Slam winner. He is a big, talented player. He is young and improving in every moment he is on the tour.”

Nadal lost in the first round in Melbourne for the first time in his career last year and, having pulled out of Wimbledon with a wrist injury, his best major result in 2016 proved to be a last-16 exit at the US Open.

The Spaniard has only played one tournament since October, reaching the quarter-finals at the Brisbane International earlier this month, but says he has “no injuries” after coming through against Baghdatis in two hours and 12 minutes.

“I can’t ask for more,” he said. “I have suffered injuries in my career, but I have had a lot of success and amazing memories from all the places I have played.

“I cannot complain. I am a lucky person and I am trying to enjoy every moment on court.”