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. 2011 Jan 1;19(1):197-210.
doi: 10.1016/j.bmc.2010.11.036. Epub 2010 Nov 25.

Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines)

Kirandeep Kaur  1 , Meenakshi Jain, Shabana I Khan, Melissa R Jacob, Babu L Tekwani, Savita Singh, Prati Pal Singh, Rahul Jain
Affiliations

Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines)

Kirandeep Kaur et al. Bioorg Med Chem. .

Abstract

In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, β-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (44, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (Plasmodiumberghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2-1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.

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Figures

Figure 1
Figure 1
8-Aminoquinolines
Scheme 1
Scheme 1
Reagents and conditions: (i) DIC, Fmoc-NH-CH(R1)-CO2H, DCM, 0 °C - rt, 4 h; (ii) 4N HCl in MeOH, rt, 45 min, 20% NH4OH or 20% piperidine in DCM, 20 min, rt; (iii) CDI, 1 or 3, DCM, rt, 5 h; (iv) Pd-C/H2, MeOH, rt, 4h or 4N HCl in MeOH, rt, 45 min or 8N HCl in MeOH, rt, 8 h.
Scheme 2
Scheme 2
Reagents and conditions: (i) DIC, R1NH-CHCOOH(CH2)n-CO2Bn, DCM, 0 °C - rt, 4 h; (ii) Pd-C/H2, MeOH, rt, 4h or 6N HCl, rt, 5h, 20%NH4OH; (iii) DIC, 1 or 3, DCM, 0 °C - rt, 4 h; (iv) 4N HCl in MeOH, rt, 45 min or 20% piperidine in DCM, rt, 20 min.
Scheme 3
Scheme 3
Reagents and conditions: (i) Et3N, 0-70 °C, 4-24 h or Et3N, 0-70 °C, THF/CH2Cl2, 4-24 h or CH2Cl2, rt, 24 h.
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References

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