Modular Synthesis and in Vitro and in Vivo Antimalarial Assessment of C-10 Pyrrole Mannich Base Derivatives of Artemisinin

Abstract

In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.

An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles

“…Compounds containing the pyrrole core have been found to possess antitumoral, antimalarial, antifungal, antibacterial and anti-HIV activity and as such, they represent interesting lead compounds for drug development. [1][2][3][4][5][6] The pharmaceutical potential of pyrrolic compounds is exemplified by the HMG-CoA reductase inhibitor atorvastatin, which has become one of the best-selling pharmaceutical products since its introduction to the global market in 1990. [7][8][9] Pyrrolic compounds continue to enter the pharmaceutical market and include molecules such as the receptor tyrosine kinase inhibitor sunitinib, approved in 2011 for the treatment of advanced neuroendocrine tumours of the pancreas.…”

Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified

“…As implicit recognition of this problem, it is countered that 'the parasite death that ensues in the presence of artemisinin is more likely to involve specific radicals and targets rather than nonspecific cell damage caused by freely diffusing oxygen-and carboncentered radical species'. [20] This begs the questions as to the nature of the radicals, the targets, and the putative role played by Fe III chelators such as desferrioxamine (DFO). [10,21] We now extend the scope of the cofactor model by examining the behavior of the artemisinins and peroxides toward LMB 8, RFH 2 10, and FADH 2 12 ( Figure 1).…”

Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity

“…The organic layer (ethyl acetate) was dried (Na 2 SO 4 ) and concentrated in vacuo to furnish the crude products. Pure DHA monomers and dimers(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) were obtained by column chromatography (silica gel) using hexane-ethyl acetate (8-5:2-5 v/v) as eluent.3-[4'-{1a'-(12aβ-Dihydroxyartemisinoxy)}-ethoxyphenyl]-1-(2", 4"-dimethoxyphenyl)-2-propen-1-one (6): Elution of the column with n-hexane-ethyl acetate (70:20) yielded a viscous compound, 90% (w/w) yield; IR ν max (neat): 1654 (chalcone), 1253, 1169, 1109 (ether), 1601, 1459, 1362, 1026, 984 (aromatics) cm -1 ; 1 H, COSY-NMR (300 MHz, Acetone-d 6 ): δ 0.84 (3H, d, J =9.3 Hz, H 3 -13a), 0.88 (3H, d, J =7.5 Hz, H 3 -14a), 1.21 (3H, s, H 3 -15a), 2.46 (1H, m, H-11a), 3.88, 3.95 (3H each, s, 2 x OCH 3 ), 3.79 (1H, m, Ha-1a'), 4.05 (1H, m, Hb-1a'), 4.27 (2H, d, J=6.3 Hz, H 2 -2a'), 4.78 (1H, d, J=3.0 Hz, αH-12a), 5.42 (1H, s, H-5a), 6.60 (1H, d, J = 2.4 Hz, H-3"), 6.64 (1H, dd, J = 8.7, 2.1 Hz, H-5"), 7.02 (2H, dd, J= 8.7, 1.8 Hz, H-3', H-5'), 7.48 (1H, d, J= 15.9 Hz, H-2), 7.58 (1H, d, J= 15.9 Hz, H-3), 7.64 (1H, m, H-6"), 7.66 (2H, d, J= 8.7 Hz, H-2', H-6'); 13 C, DEPT-NMR (75 MHz, Acetone-d 6 ): δ 12.82 (C-13a), 20.18 (C-14a), 24.64 (C-8a), 25.07 (C-2a), 25.75 (C-15a), 31.29 (C-11a), 34.96 (C-9a), 36.68 (C-3a), 37.57 (C-10a), 44.90 (C-7a), 53.00 (C-1a), 55.51, 55.79 (2 x OCH 3 ), 66.54 (C-1a'), 67.92 (C-2a'), 81.01 (C-6a, q), 87.91 (C-5a), 98.79 (C-3"), 101.99 (C12a), 103.88 (C-4a, q), 106.13 (C-5"), 115.54 (C-5', C-5'), 122.73 (C-1", q), 125.58 (C-2), 128.60 (C-1', q), 130.34 (C-2', C-6'), 132.68 (C-6"), 141.33 (C-3), 160.89 (C-2", q), 161.17…”