Malaria is one of the most dangerous diseases affecting primarily poor people of tropical and subtropical regions. The search for novel drugs against specific parasites is an important goal for antimalarial drug discovery. This study describes how 3D pharmacophores for antimalarial activity could be developed from known antimalarials and be used as screening tools for virtual compound libraries to identify new antimalarial candidates with examples of indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited in vitro activity below 100 ng/mL. These models mapped on the potent analogues and also onto other well-known antimalarial drugs of different chemical classes including quinolines, chalcones, rhodamine dyes, Pfmrk CDK inhibitors, malarial KASIII inhibitors, and plasmepsin inhibitors. The pharmacophores allowed search and identification of new antimalarials from in-house multi-conformer 3D CIS database and enabled custom designed synthesis of new potent analogues that are found to be potent against in vitro W2, D6, and TM91C235 strains of P. falciparum.