Enantiopure Indolizinoindolones with in vitro Activity against Blood‐ and Liver‐Stage Malaria Parasites

Abstract

Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.

Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists

“…In particular, the chemical shift of C7a appears ∼101.9–103.2 ppm for compounds 1 a – h and 5 a – b , diastereomers with a 3,7a‐( S , S )‐relationship. These chemical shift values are in agreement with those described earlier for similar compounds …”

“…These chemical shift values are in agreement with those described earlier for similar compounds. [13][14][15][16]…”

Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

“…SYNAP: white solid; = −54.7 o (c = 0.002, MeOH); mp: 155–156°C; 1 H‐NMR (300 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.52–7.48 (m, 2H), 7.44–7.32 (m, 5H), 7.17 (t, J = 7.5 Hz, 1H), 7.10–7.05 (m, 2H), 4.63–4.53 (m, 1H), 4.16 (dd, J = 8.8, 7.5 Hz, 1H), 3.61 (dd, J = 8.8, 6.9 Hz, 1H), 3.08 (ddd, J = 14.7, 6.3, 0.9 Hz, 1H), 2.92–2.78 (m, 1H), 2.66–2.42 (m, 3H), 2.28–2.20 (m, 1H) p.p.m. (Pereira et al, ); 13 C‐RMN (100 MHz, CDCl 3 ) δ 180.15 (C=O), 142.67 (Cq), 136.07 (Cq), 128.69 (CH), 128.27 (CH), 127.35 (Cq), 125.07 (CH), 122.08 (CH), 122.03 (CH), 119.39 (CH), 118.75 (CH), 111.62 (Cq), 111.06 (ArC), 102.35 (Cq), 72.69 (CH 2 ), 55.53 (CH), 35.01 (CH 2 ), 32.62 (CH 2 ), 29.62 (CH 2 ) p.p.m. ; Anal .…”

“…The chemical synthesis of the SYNAP enantiomer starting from ( S )‐tryptophanol, used the same protocol as described in Pereira et al . ().…”

DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties

“…Synthesis of DIMP53‐1 (Fig. A) (Pereira et al ., ; Soares et al ., ) is described in Supporting information (Scheme ; Fig. ).…”