The goal of our research endeavor was to successfully employ modern lead discovery and optimization strategies towards the development and identification of compounds possessing antimalarial activity. Preliminary data from in vitro screening at the Walter Reed Army Institute of Research identified several chemotypes including 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones to have potent antimalarial activities. Multiple synthetic routes were devised and implemented which enabled the rapid preparation and isolation of over 400 structurally diverse 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones. Our research towards discovering and optimizing antimalarials was inspired from the severe impact malaria has had on our planet especially on impoverished countries. There are over 300 million cases annually and over one million deaths. The staggering mortality rates combined with the global emergence of chemical resistance that the parasite Plasmodium falciparum has developed towards many of the common antimalarials compelled us to extend our research efforts to this growing problem. The need for identifying and developing new antimalarial drugs is very important. However, our approach focuses on the optimization of historic antimalarials such as endochin, floxacrine, or ICI 56,780 which possess liabilities such as lack of poor solubility, poor in vivo activity or lingering toxicity issues. Through these optimization efforts using both SAR and structure-property relationship (SPR) studies, a more suitable candidate was developed that had superior physicochemical properties. Our drug design approach included not only the identification of liabilities of historic compounds but also the synthesis and optimization of numerous analogs guided by SAR. All compounds were tested in vitro for antimalarial activity and characterized in parallel for physicochemical properties such as solubility, permeability, and logD7.4. Insights from both the antimalarial activity as well as the physicochemical properties determined which analogs would be advanced in the design process. Based on our early investigations, 6-chloro-7-methoxy-3-phenyl-4(1H)-quinolone emerged as a promising hit. Compared to endochin, which possesses EC50s of 8.6 nM and 46.6 nM against drug resistant strains W2 and TM90C2B, and a solubility of less than 2 µM, 6-chloro-7-methoxy-3-pheny-4(1H)-quinolone was superior with a 4-fold improvement in solubility (6 µM) as well as slightly improved antimalarial activity (EC50s of 26.2 nM and 15.3 nM against W2 and TM90C2B, respectively). Unfortunately, this compound failed to reduce parasitemia levels in P. berghei infected mice. Hit-to-lead optimization lead to the discovery of 6-chloro-7-methoxy-2-methyl-3-o-tolyl-4(1H)-quinolone which was shown to reduce parasitemia levels by 41% at day 6 post-exposure (PE) in P. berghei infected mice at a 50 mg/kg dose. The observed in vivo activity of 6-chloro-7-methoxy-2-methyl-3-o-tolyl-4(1H)-quinolone was believed to relate to the 3-fold increase in solubility (19 µM) over the 3-phenyl-susbtituted analogue. Continuation of SAR and SPR studies identified additional 4(1H)-quinolones suggesting that the microsomal stability of the compounds is as important for in vivo efficacy as the aqueous solubility. Several of the analogs that showed minimal degradation in human microsomal stability studies demonstrated increased in vivo activity in the ranges of 72-98% parasitemia reductions on day 6PE in P. berghei infected mice at 50 mg/kg. These results helped refine the final SAR and SPR optimization identifying a compound with radical curative activity in mice (99% parasitemia reductions on day 6PE in P. berghei infected mice at 50 mg/kg with five out of five mice surviving beyond 30 days). Theses studies not only highlight the effectiveness of detailed SAR and SPR strategies used in drug discovery programs, but they also showcase the importance of re-evaluating historic antimalarials and exploiting their shortcomings. These studies have opened the doors to several possibilities regarding the 4(1H)-quinolone scaffold optimization for future antimalarial development. Several of the compounds described in this work are currently being subjected to stringent head-to-head comparative studies to determine the analog best suited for pre-clinical trials.