Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives

#1 Field of the Invention

#The present invention relates to new compounds that are useful for the treatment of malaria. The compounds of the invention are pyrroloquinazolinediamine derivatives, namely alkyl derivatives, carbamate derivatives, succinimide derivatives, alkylcarboxamides derivatives, including acetamide, phthalimide, and all other amide and imide derivatives of the parent compound 1 and their analogs that are effective and less toxic for treatment of malaria, including but not limited to P. falciparum and P. vivax strains.

#2 Brief Description of Related Art

#FIGS. 1A-D are graphs showing parasitemia responses in individual rat infected with P. berghe ANKA: (A) vehicle control with 1% CMC suspension; (B) 5 mg/kg of WR288901 (3e) with 100% curative measurement; (C) 10 mg/kg of WR288901(3e) with 100% curative effect, and (D) 20 mg/kg of WR288901 (3e) with 100% curative measurement in all animals following daily intragastric administration for three days (at day 6, 7, and 8 post-inoculation) treatments (n=2−5).

#In this invention, we have initially synthesized a series of alkylcarbamates of WR227825 (2a-m) as shown in Table 1. All of the carbamates prepared, except 2-chlorobenzylcarbamate 2m, showed low in vitro activities against D-6, RCS, W-2 and TM91C235 clones of Plasmodium falciparum (Table 3), yet retained high in vivo activities against P. berghei (Table 4-5) in mouse, suggesting that carbamates of WR227825 may act as prodrugs which generate parent compound 1 in vivo. However, the carbamates all showed much higher tolerance (less toxic) than the parent molecule in the mice tests. Further, we explored the potential of carboxamides as a way to improve the therapeutic index by synthesizing a series of alkylcarboxamides and succinimides of WR227825 (Table 2) (3a-g), with which the amino groups, essential for DHFR inhibition, were tied down with acyl functions. Contrary to the existing knowledge of structure activity relation of antifolates which the free amino groups are essential for inhibitory activity, and the reported stability of amides and succinimides, the new acetamides and imides are not only highly active in in vitro tests against D-6, RCS, W-2 and TM91C235 clones of P. falciparum (IC50 ˜0.01 ng/mL) (Table 3), but also highly potent in the rodent Thompson test against P. berghei in mouse (100% cure at oral dose from <1 mg/kg to 220 mg/kg) [Tables 4 and 5]. Since amides are generally stable chemically and enzymatically in vivo, the high in vitro and in vivo efficacy of amides 3a-g were unexpected, suggesting that the amides and succinimides possess intrinsic antimalarial activity.

#TABLE 1 Pyrroloquinazolinediamine Carbamates R1 R2 R3 R4 2a H H CH3CH2OC═O H a′ CH3CH2OC═O H H H b CH3CH2OC═O H CH3CH2OC═O H c CH3CH2OC═O H CH3CH2OC═O CH3CH2OC═O d CH3CH2OC═O CH3CH2OC═O CH3CH2OC═O CH3CH2OC═O e (CH3)2CHOC═O H (CH3)2CHOC═O H f (CH3)2CHOC═O H (CH3)2CHOC═O (CH3)2CHOC═O g H H (CH3)3COC═O H h H H (CH3)3COC═O (CH3)3COC═O i H (CH3)3COC═O (CH3)3COC═O (CH3)3COC═O j (CH3)3COC═O (CH3)3COC═O (CH3)3COC═O (CH3)3COC═O k H H (CH3)2CHCH2OC═O H l (CH3)2CHCH2OC═O H (CH3)2CHCH2OC═O H m H H

#Among the compounds synthesized, two of the best derivatives (2b and 3e) with the best antimalaria activity against P. berghei in mice were further tested against P. berghei in rats, P. yoelii in mouse, P. cynomolgi in Rhesus monkey and P. falciparum and P. vivax in Aotus monkeys. Compound 3e produced 100% cure against P. berghei in rats at doses of 5, 10 and 20 mg/kg×3 administered orally [FIG. 1]. Against P. yoelii in sporozoite challenged mouse, 3e completely prevented parasitemia formation at doses from 0.65 to 40 mg/kg given orally for 3 consecutive days [Table 6].