there are a few safari parks in the south where you don't need malaria pills. You could try driving along the garden route from Cape Town, though I don't know why it's called that, it's not gardeny but it's often very dramatic. George and Knysna are nice places to stay.
The best reason for going to Joburg would be driving (about 300 miles) to the Kruger reserve; but I'm not sure I'd do it. As 237SJ says, Joburg's not a place you feel very safe in.
The Cape Town area is excellent, though: scenery, botany, wine making, whale watching, safari parks within reach.