Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

Abstract

Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure-activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.

Keywords: Human African Trypanosomiasis (HAT); Trypanosoma brucei; acetogenin; natural product analogues; neglected diseases; stereochemistry.

Figure 1

Current drugs for treatment of Human African trypanosomiasis.

Figure 2

Rationale for simplified analogue design.

Figure 3

Molecular modelling of the lowest energy conformations for a) chamuvarinin (6), b) syn-syn triazole (18a) and c) anti-anti triazole (20a).

Scheme 1

Synthesis of azides 11a-c, 12 and 13 and alkynes 16a-b and 17a-b: a) CH₂CHCH₂CH₂MgBr, CuI, THF, −40 °C ✶ RT; b) mCPBA, CH₂Cl₂, 0 °C ✶ RT; then (±)-CSA (20 mol%), RT; c) PPh₃, iPr₂NEt, DIAD, DPPA, 0 °C ✶ RT; d) (COCl)₂, DMSO, CH₂Cl₂, Et₃N, −78 °C ✶ RT; e) dimethyldiazo-2-oxopropylphosphonate, K₂CO₃, MeOH, RT; f) CBr₄, PPh₃, CH₂Cl₂, 0 °C then −78 °C; g) n-BuLi, THF, −78 °C. mCPBA = 3-chloroperbenzoic acid, (±)-CSA = (±)-camphorsulfonic acid, DIAD = diisopropyl azodicarboxylate, DPPA = diphenyl phosphoryl azide, DMSO = dimethyl sulfoxide.

Scheme 2

Synthesis of triazole analogues 18a-d, 19a-b, 20a-b, 21a-b and 22: a) CuSO₄·5H₂O, Na ascorbate, H₂O, t-BuOH, RT.

Scheme 3

Synthesis of alcohols 23-28: a) 20% Pd(OH)₂/C, H₂ (1 atm), EtOH, RT.

Scheme 4

Synthesis of triazoles 31 and 32: a) 1H-mercaptophenyltetrazole, PPh₃, DIAD, 0 °C; b) (NH₄)₆Mo₇O₂₄·4H₂O, H₂O₂, EtOH, 0 °C → RT; c) NaHMDS, THF, −78 °C; then 30, THF −78 → −20 °C; d) TsNHNH₂, NaOAc, DME, H₂O, 100 °C. PT = phenyl tetrazole, NaHMDS = sodium hexamethyldisilylazide, DME = dimethoxyethane.

Scheme 5

Synthesis of advanced alcohol 34: a) TBAF, THF, 0 °C → RT; b) 1H-mercaptophenyltetrazole, PPh₃, DIAD, 0 °C; c) (NH₄)₆Mo₇O₂₄·4H₂O, H₂O₂, EtOH, 0 °C → RT; d) NaHMDS, THF, −78 °C; then 30, THF −78 → −20 °C; e) TsNHNH₂, NaOAc, DME, H₂O, 100 °C; f) BCl₃·SMe₂, CH₂Cl₂, −78 °C → RT; g) 20% Pd(OH)₂/C, H₂ (1 atm), EtOH, RT. TBAF = tetrabutylammonium fluoride.