Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines

Abstract

We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.

Figure 1

Structures of primaquine (1) and promising 8-quinolinamines 2–3

Figure 2

General structure of the newly synthesized 8-quinolinamines

Scheme 1. Reagents and conditions

(i) (CH₃)₃CCO₂H, AgNO₃, (NH₄)₂S₂O₈, 10% H₂SO₄, CH₃CN, 70 °C; (ii) raney Ni, EtOH, H₂, 45 psi, 45 min; (iii) 2-(4-bromopentyl)-1,3-isoindolinedione, Et₃, 120 °C, 24 h; (iv) NH₂NH₂.H₂O, EtOH, reflux, 8 h; (v) suitably N- and side-chain protected L/D-amino acid, DCC, DCM, rt, 6 h; (vi) H₂/Pd-C, MeOH, 1h, rt or 4N HCl-MeOH, 1h, rt or 30% HBr-AcOH, 45 min, rt.

Scheme 2. Reagents and conditions

(i) 1-chloro-3-pentanone, 85% o-H₃PO₄, As₂O₅, 80 °C, 3 h; (ii) raney nickel, EtOH, H₂, 45 psi, 45 min; (iii) 2-(4-bromopentyl)-1,3-isoindolinedione, Et₃N, 120 °C, 24 h; (iv) NH₂NH₂.H₂O, EtOH, reflux, 8 h; (v) suitably N- and side-chain protected L/D-amino acid, DCC, DCM, rt, 6 h; (vi) H₂/Pd-C, MeOH, 1h, rt or 4N HCl-MeOH, 1h, rt or 30% HBr-AcOH, 45 min, rt.