Malaria Box-Inspired Discovery of -Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Mar 18

PMID 35300096

Authors

Jopaul Mathew

Sha Ding

Kevin A Kunz

Emily E Stacy

Joshua H Butler

Reagan S Haney

Emilio F Merino

Grant J Butschek

Zaira Rizopoulos

Maxim Totrov

Maria B Cassera

Paul R Carlier

Affiliations

Soon will be listed here.

Abstract

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite . Interestingly, , a minor byproduct of these syntheses, proved to be potent against and was orally efficacious (40 mg/kg) in an mouse model of malaria.

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References

Bowman J, Merino E, Brooks C, Striepen B, Carlier P, Cassera M . Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box. Antimicrob Agents Chemother. 2013; 58(2):811-9. PMC: 3910863. DOI: 10.1128/AAC.01500-13. View

Ding S, Ghavami M, Butler J, Merino E, Slebodnick C, Cassera M . Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints. Bioorg Med Chem Lett. 2020; 30(22):127520. PMC: 7686247. DOI: 10.1016/j.bmcl.2020.127520. View

Gamo F, Sanz L, Vidal J, de Cozar C, Alvarez E, Lavandera J . Thousands of chemical starting points for antimalarial lead identification. Nature. 2010; 465(7296):305-10. DOI: 10.1038/nature09107. View

Ross A, Lang H, Jackson R . Much improved conditions for the Negishi cross-coupling of iodoalanine derived zinc reagents with aryl halides. J Org Chem. 2009; 75(1):245-8. DOI: 10.1021/jo902238n. View

Ghavami M, Merino E, Yao Z, Elahi R, Simpson M, Fernandez-Murga M . Biological Studies and Target Engagement of the 2- C-Methyl-d-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1 R,3 S)-MMV008138 and Analogs. ACS Infect Dis. 2017; 4(4):549-559. PMC: 5899049. DOI: 10.1021/acsinfecdis.7b00159. View

Imlay L, Armstrong C, Masters M, Li T, Price K, Edwards R . IspD (2-C-Methyl-D-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target. ACS Infect Dis. 2016; 1(4):157-167. PMC: 4714788. DOI: 10.1021/id500047s. View

Wu W, Herrera Z, Ebert D, Baska K, Cho S, DeRisi J . A chemical rescue screen identifies a Plasmodium falciparum apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis. Antimicrob Agents Chemother. 2014; 59(1):356-64. PMC: 4291372. DOI: 10.1128/AAC.03342-14. View

Spangenberg T, Burrows J, Kowalczyk P, McDonald S, Wells T, Willis P . The open access malaria box: a drug discovery catalyst for neglected diseases. PLoS One. 2013; 8(6):e62906. PMC: 3684613. DOI: 10.1371/journal.pone.0062906. View

Cagasova K, Ghavami M, Yao Z, Carlier P . Questioning the γ-gauche effect: stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using H-H coupling constants. Org Biomol Chem. 2019; 17(27):6687-6698. PMC: 6628257. DOI: 10.1039/c9ob01139k. View

10.

Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M . Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science. 1999; 285(5433):1573-6. DOI: 10.1126/science.285.5433.1573. View

11.

Kamal A, Tangella Y, Lakshmi Manasa K, Sathish M, Srinivasulu V, Chetna J . PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-β-carbolines: synthesis of norharmane, harmane, eudistomin U and eudistomin I. Org Biomol Chem. 2015; 13(32):8652-62. DOI: 10.1039/c5ob00871a. View

12.

Yeh E, DeRisi J . Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. 2011; 9(8):e1001138. PMC: 3166167. DOI: 10.1371/journal.pbio.1001138. View

13.

Yao Z, Krai P, Merino E, Simpson M, Slebodnick C, Cassera M . Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies. Bioorg Med Chem Lett. 2015; 25(7):1515-9. PMC: 4374032. DOI: 10.1016/j.bmcl.2015.02.020. View