A new class of selective HIV-1 IN-LEDGF/p75 inhibitors without carboxylic acid/bioisostere are identified through scaffold hopping. The 3-hydroxypicolinamides function as dual HIV-1 IN inhibitors targeting IN-LEDGF/p75 interaction and IN dimerization with anti-HIV effect. The binding mode of the novel IN-LEDGF/p75 inhibitors was established through shape-based ROCS pharmacophore model.