Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

Abstract

Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…The 4‐aminoquinazoline scaffold is present in a number of human tyrosine kinase inhibitors including lapatinib ( 496 ), which has itself demonstrated in vitro antiplasmodial activity . However, antiplasmodial activity is seemingly enhanced through the introduction of a 2‐amino substituent (e.g., 497 ) analogous to that observed on the antiplasmodial thienopyrimidines.…”

Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD- scid IL2Rγ null Mouse Model of Malaria

“…Compounds 1 to 4 (Fig. 1) were previously evaluated against P. falciparum (8) using the lactate dehydrogenase (LDH)-based assay format (23). To ensure the consistency of EC 50 values obtained by the different assay technologies, we determined the EC 50 values of the lead compounds against P. falciparum in three previously described assay formats: the LDH (10) and hypoxanthine (24) assays and SYBR green fluorescence flow cytometry (25).…”

“…To contribute to the global fight against malaria, we previously disclosed preliminary findings on the antimalarial activities of the 2-anilinoquinazoline class (8). This class was identified by analyzing publicly disclosed data from high-throughput screens against multiple life cycle stages of the Plasmodium parasite (9-12).…”

“…We recently described the optimization of the antimalarial activity of the 2-anilinoquinazoline class (8). In this study, we defined the structure-activity relationship to generate early lead compounds WEB-484 to WEB-487, known herein as compounds 1 to 4, respectively ( Fig.…”

Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

“…Recently, high throughput screens (HTS) followed by the design and synthesis of new structures revealed several analogues possessing the 2-anilino quinazoline scaffold, such as the disubstituted quinazolines C-D, BIX-01294, and TM2-115 ( Figure 1). In addition, the quinoline-4carboxamide series was also identified from a screen against the P. falciparum 3D7 strain leading to the discovery of quinolines E and DDD107498 (Figure 1) [19][20][21][22][23] .…”