Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure–Activity and Structure–Property Relationship Studies

Abstract

Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

“…Both assay methods indicate that compound 22 displays no cross-resistance with CQ-resistant strains. As noted above, quinolones act against the Pf cytochrome bc 1 complex and display cross-resistance with atovaquone-resistant Pf 25,61 ; for DQ, this is attributed to partial binding within the ubiquinol-binding site carrying one or more of the resistance mutations 30 . Thus, according to Table 3, cross-resistance is also observed for the DQ derivative 22.…”

Total Synthesis of (±)-Decursivine via BINOL-Phosphoric Acid Catalyzed Tandem Oxidative Cyclization

“…In continuation of our work towards antimalarial heterocyclic compounds [12][13][14][15] and indole-containing natural products, [16][17][18][19] we report a 5 steps total synthesis of (±)-decursivine, an antimalarial indole alkaloid from inexpensive and commercially available simple starting materials. Our retrosynthetic plan is illustrated in gure 2.…”

New Quinolone-Based Thiosemicarbazones Showing Activity Against Plasmodium falciparum and Mycobacterium tuberculosis

“…Briefly, the reduction of p -nitroacetophenone 6 using reduced iron powder and ammonium chloride in refluxing ethanol afforded p -aminoacetophenone 7 . Compound 7 was condensed with diethyl ethoxy methylenemalonate, and following a classical Gould-Jacobs cyclization procedure for quinolone synthesis [32], later cyclised in boiling diphenylether to obtain intermediate 8 in 50–70% yields. Compound 8 , just like most quinolones reported in literature, is practically not soluble in any solvent [32]; this partly could be attributed to pi - pi stacking promoted by the highly planar nature of this fragment in particular, and the quinolone nucleus in general.…”

“…Compound 7 was condensed with diethyl ethoxy methylenemalonate, and following a classical Gould-Jacobs cyclization procedure for quinolone synthesis [32], later cyclised in boiling diphenylether to obtain intermediate 8 in 50–70% yields. Compound 8 , just like most quinolones reported in literature, is practically not soluble in any solvent [32]; this partly could be attributed to pi - pi stacking promoted by the highly planar nature of this fragment in particular, and the quinolone nucleus in general. It was therefore essential to modify this fragment in such a way as to disrupt planarity, and/or introduce hydrophilic moieties before appending a thiosemicarbazone unit, this was achieved through N -alkylation of the secondary amine and aminolysis of the ester functionalities in 8 .…”