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. 2020 Mar 17;5(12):6967-6982.
doi: 10.1021/acsomega.0c00327. eCollection 2020 Mar 31.

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

Rudolf Mueller  1 , Virsinha Reddy  1 , Aloysius T Nchinda  1 , Fanuel Mebrahtu  1 , Dale Taylor  2 , Nina Lawrence  2 , Lloyd Tanner  2 , Marine Barnabe  2 , Charles J Eyermann  1 , Bin Zou  3 , Ravinder R Kondreddi  4 , Suresh B Lakshminarayana  5 , Matthias Rottmann  6   7 , Leslie J Street  1 , Kelly Chibale  1   8
Affiliations

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

Rudolf Mueller et al. ACS Omega. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Pharmacologically active molecules containing the benzimidazole structure.
Scheme 1
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
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
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
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
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
Figure 2
Exploration of SAR studies based on lead compound 3.
Figure 3
Figure 3
P. falciparum SCID mouse efficacy study for compound 3 compared with chloroquine (CQ).
Scheme 6
Scheme 6. Overview of the SAR Trends of the Series
See this image and copyright information in PMC

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