Antimalarial Cation‐dimers Synthesized in Two Steps from an Inexpensive Starting Material, Isonicotinic Acid

Abstract

Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low-cost antimalarials, the MAP series 6-10, bis-cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis-cation-type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1,1'-(1,12-dodecanediyl)bis[4-[(buthylamino)carbonyl]pyridinium bromide], MAP-412 (6 d), exhibited a potent antimalarial activity (ED(50)=8.2 mg kg(-1)). Being prepared at low cost, our bis-cation-type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.

Synthesis and properties of cationic surfactants with tuned hydrophylicity

“…Pyridinium surfactants [1], in particular, are important as ingredients of cosmetic products [2], and are also used as corrosion inhibitors [3], in emulsion polymerization [4] and textile processing [5]. Within biological applications, they show a good antimicrobial activity [6] and can be used as drugs [7], gene delivery agents [8] or in DNA extraction methods [9]. Quite recently, cationic pyridinium surfactants have found applications in the synthesis of TiO 2 nanoparticles [10], in ionic liquids synthesis [11] or as electrolytes for dye-sensitized solar cells [12].…”

Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions?

“…[74] The subsequently designed MAP series showed increased activities with increased alkyl chain linker length, whereas the cytotoxicity of the compounds increased with the number of side methylene groups (m). [75] A lead compound, MAP-412 (n = 12, m = 4; see Figure 7), exhibited an IC 50 value of 100 nm with no cytotoxicity and an ED 50 value of 8.2 mg kg À1 in mice infected with P. berghei. [75] The inhibitory effect of the cyanobacterium-derived alkaloid nostocarboline ( Figure 7) against protozoan parasites was described.…”

“…[75] A lead compound, MAP-412 (n = 12, m = 4; see Figure 7), exhibited an IC 50 value of 100 nm with no cytotoxicity and an ED 50 value of 8.2 mg kg À1 in mice infected with P. berghei. [75] The inhibitory effect of the cyanobacterium-derived alkaloid nostocarboline ( Figure 7) against protozoan parasites was described. [76] Biscationic dimeric derivatives exhibited activities against Leishmania donovani in the sub-micromolar range, against Trypanosoma brucei in the low-micromolar range, and against P. falciparum in the low-nanomolar range with weak cytotoxicity.…”

Surface, aggregation properties and antimicrobial activity of four novel thiourea-based non-ionic surfactants

“…The solid product obtained was filtered and washed with doubly distilled water for further purification. The compounds obtained were dried in air and recrystallized from ethanol [19,20]. Full synthetic details and spectroscopic characterizations are provided in Table 1 and Supporting Information.…”