Caelestines A–D are brominated 4-quinolone-2-carboxylic acids (4Q2Cs) first isolated from the Australian ascidian Aplidium caelestis in 2010. The caelestines are analogues of the neuroactive tryptophan metabolites, kynurenic acid and xanthurenic acid, the latter of which induces gametogenesis in Plasmodium parasites. Caelestines are also structurally similar to important antimalarial quinolines and fluoroquinolone antimicrobial drugs. A convenient methodology exists for the Conrad-type synthesis of 4Q2Cs from substituted anilines and acetylene dicarboxylates cyclized in polyphosphoric acid with catalytic methane sulfonate. Here, we report the synthesis of caelestines A–C using this methodology, constituting the first de novo syntheses of caelestines B and C, together with optimisation and chromatographic studies. Structure-activity relationship (SAR) trends regarding the in vitro antimalarial activity and selectivity of the caelestines A–C and six other related quinolones, including 5 novel quinolones, against Plasmodium falciparum 3D7 and PfDd2 were also explored.