Structure–Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro

Abstract

In the context of drug repositioning and expanding the existing structure−activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (Pf NF54 IC 50 = 0.025−0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; Pf LG IC 50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model

“…Interestingly, the N -methyl analogue ( 16 , Pf NF54 IC 50 = 0.033 μM) and truncation of the benzyl group ( 15 , Pf NF54 IC 50 = 0.055 μM) produced compounds with high activity and high solubility (>80 μM). Previously, this change drastically reduced activity in analogues containing a cyano (CN) group in place of the oxadiazole ring …”

“…Analogues 6 – 13 (SAR 1, Scheme ) and 15 – 24 (SAR 2, Scheme ) were synthesized by coupling phenethyl bromides 2 – 4 or commercially sourced alkylating agents to previously reported amine intermediates 5 and 14a , b , respectively (Scheme ). Compound 17 was prepared from isopropyl intermediate 14c , which had been synthesized following previously reported synthetic procedures …”

“…An ester-containing AST analogue 1 (Figure 2) emerged with high in vitro Pf activity and favorable solubility from our recent work; however, and unsurprisingly, it had poor microsomal metabolic stability. 12 This prompted an optimization campaign to improve microsomal metabolic stability toward identifying an AST analogue for PoC studies. While various strategies are known to address the metabolic liability associated with the ester group, bioisosterism is one of the most common approaches for hydrolysis-labile groups such as esters.…”

Systematic Analysis of Clemastine, a Candidate Apicomplexan Parasite-Selective Tubulin-Targeting Agent

“…The activity of astemizole was a surprise to us; we chose it as a likely negative control for the testing cascade. Astemizole is also an obsolete antihistamine that has been shown to target heme detoxification in Plasmodium parasites [ 22 , 23 , 24 ]. Because this pathway is specific to hemoglobin-degrading malaria parasites, we anticipated that astemizole would be inactive or less active against Toxoplasma .…”

“…Targeting multiple proteins within the tubulin biogenesis and microtubule assembly pathway could prevent the emergence of drug-resistant parasites. In addition to clemastine, we also evaluated oryzalin, a well-defined selective inhibitor of protozoan tubulin, and astemizole, a distinct antihistamine with multiple mechanisms of anti-parasitic activity, including inhibition of heme detoxification in Plasmodium [ 22 , 23 , 24 ].…”