Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure-Activity Relationship Studies, and Biological Assessment

Abstract

A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC₅₀ NF54 = 0.81 μM) and its methyl-substituted analogue 2 (IC₅₀ NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC₅₀ NF54 = 0.062 μM) and multidrug-resistant K1 (IC₅₀ K1 = 0.054 μM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.

Figure 1

Pharmacologically active molecules containing the benzimidazole structure.

Scheme 1. General Synthetic Approach to the Synthesis of 2-Amino Benzimidazole Derivatives

Reagents and conditions: (a) Et₃N, acetonitrile (ACN), 50 °C, 16 h (56–97%) or K₂CO₃, dimethylformamide (DMF), 80 °C, 4–18 h (25–98%) or K₂CO₃, dimethyl sulfoxide (DMSO), 120 °C, 24 h, (93%); (b) Pt/C, H₂ balloon, RT, MeOH, 8 h to 3 days (88–97%) or Fe powder, sat. aqu. NH₄Cl, EtOH, 90 °C, 6–18 h (69–97%) or NH₂NH₂·H₂O, MeOH, 80 °C, 2 h (61%); (c) triphosgene, dichloromethane (DCM), 25 °C, 16 h (68–94%); (d) POCl₃, HCl, 150 °C, 4–24 h, (44–51%) or POCl₃, PCl₅, 110 °C, 1 h (45%); (e) CH(OMe)₃, HCOOH, 100 °C 1–2 h (30–85%) or CH(OEt)₃, para-toluene sulfonic acid (PTSA), tetrahydrofuran (THF), reflux, 2 h (88%); (f) lithium diisopropylamide (LDA), Cl₃C–CCl₃, THF, −78 °C, 4–5 h (33–96%) or LDA, CBr₄, THF, −78 °C, 3 4 h (41%); (g) R³R⁴NH, Et₃N, t-BuOH, 120 °C, 6 h to 18 days (9–91%).

Scheme 2. General Synthetic Route for the 2-Amino Benzimidazole Analogues (43)

Reaction and conditions: (a) R⁵-CHO, Na(OAc)₃BH, AcOH, DCM, 20–27 °C, 2–24 h (16–49%).

Scheme 3. General Synthetic Route for the C-Linked Benzimidazoles 46

Reagents and conditions: (a) HATU, DIPEA, DMF, 35 °C, 16 h (39–94%); (b) AcOH, 100 °C, 6 h (28–71%).

Scheme 4. General Synthetic Route for the Synthesis of 5-Substituted (49) and 4,5-Disubstituted 2-Amino Benzimidazoles (52)

Reaction and conditions: (a) R¹⁰-B(OH)₂, Cs₂CO₃, Pd(dppf)Cl₂, 1,4-dioxane/H₂O (4:1), 95 °C, 4–24 h (45-97%); (b) 4 N HCl in 1,4-dioxane, 2–4 h, 20–27 °C (15–76%); for 49ea; R¹⁰ = 4-Py; EtOAc, neutralized with sat. NaHCO₃ solution, 20 °C, 3 h (50%).

Scheme 5. Synthetic Route for the Synthesis of Imidazopyridines (57)

Reagents and conditions: (a) (i) Bn-NH₂, K₂CO₃, DMF, 80 °C, 3–4 h, quantitative; (b) (i) Pt/C, H₂ balloon, 20 °C, MeOH, 2–3 h; (ii) CH(OMe)₃, HCOOH, 100 °C, 1–2 h (30–82%); (c) LDA, Cl₃C–CCl₃, THF, −78 °C, 4 h (37–91%); (d) piperazine, Et₃N, t-BuOH, 120 °C, 18 h (25–80%).

Figure 2

Exploration of SAR studies based on lead compound 3.

Figure 3

P. falciparum SCID mouse efficacy study for compound 3 compared with chloroquine (CQ).

Scheme 6. Overview of the SAR Trends of the Series