Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation

Abstract

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Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases

“…As drug resistance to frontline antimalarials continues to proliferate, there is an urgent need to generate new agents toward novel drug targets (21). Plasmodium M1 and M17 aminopeptidases are validated targets for the design of novel anti-malarial agents, and the subject of ongoing structure-based drug design programs (8)(9)(10)(11)(22)(23)(24)(25). The development of potent and selective inhibitors requires a thorough characterization and comparison of how the target aminopeptidases function.…”

Driving antimalarial design through understanding of target mechanism

“…10 and 14) [88][89][90][91] and while they exhibited excellent ZBG properties for coordination, these moieties often suffer from permeability issues and were produced largely as tool compounds. As a result, more recent compounds utilise groups like hydroxamic acids (9, 11, and 12, this type of coordination is demonstrated in Figure 3B) [90][91][92][93][94][95] and geminal-diol (13) [96][97][98] for the coordination of Zn 2+ . Although targeting the Zn 2+ is essential, the approach raises challenges for selectivity of the parasite target over human homologuesparasite specific inhibitors therefore require the employment of specific interactions with the PfA-M1 S1 and S1 0 subsites [81].…”

“…More recently, a series of aminobenzosuberone inhibitors (e.g. 13) with selective PfA-M1 inhibition over other MAPs were reported [96][97][98].…”

Metalloaminopeptidases of the Protozoan Parasite Plasmodium falciparum as Targets for the Discovery of Novel Antimalarial Drugs

“…Addition of chemical moieties to the phenyl ring to extend T5 into this pocket may enable further interactions, for example with Glu526 which points into the active site. 72 This information may be employed to drive the synthesis of future T5 analogues. Image generated using PyMOL.…”

“…102 Unfortunately, T5 demonstrated high clearance (43 mL/min/kg) and a relatively short half-life (T1/2) of 2.2 hours following intravenous dosing to female CD-1 mice. 72 The high level of clearance from mice, coupled with solubility issues, represent key areas to focus on for the further development of aminobenzosuberone derivatives.…”