The bases differ mostly in how far you have to walk after dark and whether you want to eat where you sleep.
Barrio Amón — coffee-boom houses, quiet nights
Just north of the centre, full of late-19th-century mansions converted into small hotels, and ten minutes on foot from the main museums. Very quiet after dark, which is either the reason to stay or the reason not to.
Barrio Escalante and Los Yoses — eat downstairs
East of the centre, in the restaurant and bar district, where you can walk to dinner and walk back — rare in this city. Further from the museums, so you take a bus or a taxi in each morning.
Centro — cheapest, closest, least comfortable
Around Avenida Central you are minutes from the Teatro Nacional, the markets and the museum cluster, and this is where the cheap hotels are. The streets west towards the old Coca-Cola bus area empty out at night and are best avoided on foot.
Sleep near the terminal you leave from
Long-distance buses go from a dozen scattered terminals rather than one station, and several leave before dawn. If you have a 5am Caribbean or Pacific departure, pick somewhere within walking distance of that specific terminal instead of crossing the city in the dark.