Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

Abstract

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC₅₀ values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.

Figure 1

Molecular structures of known antimalarial agents.

Figure 2

Structures of synthesized ART–endoperoxide GMeP (5), ART–ACQ (6 and 7) and ACQ–endoperoxide GMeP (8) hybrids, and ART–Spd and – Hsd mixed conjugates with endoperoxide GMeP and ACQ (9, 10 and 11, 12, respectively) and endoperoxide GMeP–Spd and −Hsd mixed conjugates with ACQ (13 and 14).

Scheme 1. Synthesis of ART–Endoperoxide GMeP (5), ART–ACQ (6 and 7) and ACQ–Endoperoxide GMeP (8) hybrids

Reagents and reaction conditions: (i) HBTU, DIPEA, CH₂Cl₂, 0 °C to rt, 3–12 h.

Scheme 2. Synthesis of ART–Spd and −Hsd Mixed Conjugates with Endoperoxide GMeP or ACQ (9-12) and Endoperoxide GMeP–Spd and −Hsd Mixed Conjugates with ACQ (13 and 14)

Reagents and reaction conditions: (i) HBTU, DIPEA, CH₂Cl₂, 0 °C to rt, 3–12 h; (ii) succinic anhydride, DMAP, CH₂Cl₂, 0 °C to rt, 12 h; (iii) 3–6% TFA in CH₂Cl₂, CF₃CH₂OH, 0 °C, 2–12 h.