Diastereoselective Synthesis of Potent Antimalarial Cis-β-lactam Agents

Aliasghar Jarrahpour (1) , Maryam Rostami (1) , Véronique Sinou (2) , Christine Latour (2) , Lamia Djouhri-Bouktab (3) , Jean Michel Brunel (3)

1 Shiraz University - Shiraz University
2 IP-TPT - Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques
3 CRCM - Centre de Recherche en Cancérologie de Marseille

Fifteen novel β-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2-aminoethyl) β-lactams 6a-o were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of cis-β-lactam derivatives. These newly synthesized β-lactams were evaluated for their antimalarial activity against p. falciparum K14 resistant strain and showed good to excellent EC 50 values. Of the thirty β-lactams tested, 5 h, 6a and 6c showed IC 50 < 20 µM while 5b, 5c, 5e, 5f, 5g, 5i, 5j, 6d, 6g and 6h exhibited IC 50 <50. Compounds 5c, 5h, and 5q-t were examined for their anticancer properties against K562 Leukemia cell line and 5s showed the best activity. Compounds 3a-j, 5a-o, 6a-o, were tested against S. aureus , E. coli, C. albicans and showed no activity below 125 µg/mL.

Keywords: Staudinger; Antimalarial activity; N-(2-aminoethyl) β-lactams;tert-butyl; carbamate; 2-Azetidinones; P.falciparum

Domains: Chemical Sciences; Chemical Sciences; Organic chemistry; Life Sciences [q-bio]; Life Sciences [q-bio]; Microbiology and Parasitology; Life Sciences [q-bio]; Microbiology and Parasitology; Bacteriology; Life Sciences [q-bio]; Microbiology and Parasitology; Parasitology

Aliasghar Jarrahpour, Maryam Rostami, Véronique Sinou, Christine Latour, Lamia Djouhri-Bouktab, et al.. Diastereoselective Synthesis of Potent Antimalarial Cis-β-lactam Agents. Iranian Journal of Pharmaceutical Research, 2019, 18 (2), pp.596-606. ⟨10.22037/ijpr.2017.2024⟩. ⟨hal-02392424⟩