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Synthesis of triazole-type harmiquins

Background Malaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most widespread and deadliest diseases worldwide with estimated 229 million clinical cases and 409 000 deaths in 2019. Despite significant efforts, effective vaccines against malaria are not available. Additionally, the existing antimalarials are progressively losing their efficacy due to the development of drug resistance. Thus, there is a vital need for new and potent antimalarials. Aims A recent rational approach in antimalarial drug design involves synthesis of molecular hybrids containing two different scaffolds with antimalarial properties. Herein, we present harmiquins, hybrids constituted of harmine, a naturally occurring beta-carboline with confirmed antimalarial activity, and 7-chloroquinoline, a moiety with pronounced antimalarial properties. Methods In this work “click” chemistry approach, i.e. Cu(I) catalysed alkyne-azide cycloaddition, was selected as a method of choice for linking harmine and 7-chloroquinoline moiety. In the preparation of the required alkynes and azides various synthetic methods were applied, including green procedures. In particular, conventional heating was replaced by microwave-assisted reaction whenever possible to reduce reaction times and increase the yields of the products obtained. Progress of chemical reactions was monitored by TLC. Products were purified by column chromatography/recrystallization. Structures of novel harmiquins were confirmed by 1H and 13C NMR, IR and MS. All chemicals were acquired from commercial sources. Results To prepare the title hybrids, we have synthesized 7-chloroquinoline-based alkyne 1 and azides 2, 4, as well as β-carboline-based azides 5, 6 and alkynes 7-9. Alkyne 1 was prepared by the treatment of 4, 7-dichloroquinoline with glacial acetic acid and subsequent alkylation of the obtained phenol using propargyl bromide and Cs2CO3. Synthesis of azide 2 was straightforward, via nucleophilic substitution of 4, 7-dichloroquinoline with NaN3, whereas preparation of azide 4 included two-step procedure. The first step included reaction of 4, 7-dichloroquinoline with 4-aminobutanol in the presence of triethylamine (TEA). The obtained alcohol 3 was successfully converted to azide using 2-azido-1, 3-dimethyl-imidazolinium hexafluorophosphate (ADMP) and base 1, 8- diazabicyclo(5.4.0)undec-7-ene (DBU). Beta-carboline-based azides 5, 6 and alkyne 7 were prepared in a multi-step reaction pathway, starting from tryptamine or its analogues. Pictet-Spengler condensation of: 1) tryptamine with 2, 2- dimethoxyacetaldehyde, 2) tryptophan methyl ester with acetaldehyde dimethylacetal, and 3) 5- methoxytryptamine with acetaldehyde dimethylacetal, followed by oxidation of tetrahydro-beta-carboline intermediates, provided corresponding beta-carbolines substituted at positions C-1, C-3 and C-6, respectively. Acetal group at C-1 was hydrolyzed in a mixture of AcOH/H2O, and the obtained aldehyde reduced to alcohol using LiAlH4. Reduction under similar conditions was applied for the transformation of ester group at C-3 to alcohol. Ultimately, alcohols were converted to azides 5, 6 using ADMP and DBU. Ether group at position 6 was hydrolyzed in a mixture of CH3COOH/HBr affording phenol, which was alkylated using propargyl bromide in presence of Cs2CO3 to generate alkyne 7. On the other hand, synthesis of alkynes at C-7 and N-9 was carried out starting from commercially available harmine. Harmine was alkylated at the position N-9 using propargyl bromide and Cs2CO3 giving rise to alkyne 9. At the same time, harmine was converted to harmole in the reaction with CH3COOH/HBr. Harmole was successfully alkylated using the same reagents and similar reaction conditions providing alkyne 8. Synthesized alkynes and azides were the starting compounds for “click” reactions that resulted in triazoltype harmiquins. ‘Click’ reactions proceeded smoothly using Cu(II)-acetate precatalyst in methanol, giving hybrids in good yields. Conclusion Our synthetic routes afforded 8 novel harmiquins, harmine-7-chloroquinoline hybrids. Antiplasmodial activity of the prepared hybrids will be screened in vitro against the erythrocytic and hepatocytic stages of the Plasmodium life cycle. Cytostatic activity will be tested as well, on a panel of human cancer cell lines(HepG2, HCT116, SW620, MCF-7, Hek293).

malaria, hybrid compound, harmine, chloroquine, triazole,

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