Antimalarial effect of bis-pyridinium salts, N,N′-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

Fujimoto, Kanji; Morisaki, Daiki; Yoshida, Minoru; Namba, Tatsuji; Kim, Hye‐Sook; Wataya, Yusuke; Kourai, Hiroki; Kakuta, Hiroki; Sasaki, Kenji

doi:10.1016/j.bmcl.2006.02.030

Cited by 35 publications

(13 citation statements)

References 5 publications

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“…General procedure for synthesis of quaternary pyridinium compounds Hydroxyiminomethylpyridine (1 mmol) and the alkylating agent (1.5 mmol) in solvent (20 mL) were stirred at 60-80°C for 1-24 h. The mixture was cooled to room temperature, the precipitate was collected, washed with acetone (3 · 20 mL), dried under vacuum, and characterized by 1 H NMR, 13 C NMR, ESI-MS and IR (19). Spectral data for representative compounds are as follows: (Bromothiophen-2-yl)-methyl-2-hydroxyiminomethylpyridinium chloride (1)(2)(3)(4)(5)(6)9), antimalarial (7,8,(10)(11)(12)(13)(14), and antileishmanial (15) pyridinium salts ⁄ dications.…”

Section: Methodsmentioning

confidence: 99%

Antimicrobial, Antimalarial, and Antileishmanial Activities of Mono‐ and Bis‐quaternary Pyridinium Compounds

Bharate

Thompson

2010

Chem Biol Drug Des

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Pyridinium-based oxime compounds have been utilized worldwide as antidotes following exposure to anticholinesterase agents. In the event of combined chemical and biological incident, it is of vital importance to know the ability of antidotes to provide additional protection against biological threats. This paper reports results of in vitro antimicrobial and antiprotozoal activities of a series of quaternary pyridinium oximes against a number of lower pathogenicity BSL-1 and 2 agents. In general, our compound panel had little to no antimicrobial action except for thiophene- and benzothiophene-substituted monoquaternary pyridinium compounds 21 and 24 that showed moderate antibacterial activity against Staphylococus aureus and methicillin resistant S. aureus with IC50 values ranging from 12.2–17.7 µg/mL. Compounds 21 and 24 also exhibited antileishmanial activity against Leishmania donovani with IC50 values of 19 and 18 µg/mL, respectively. Another monoquaternary pyridinium compound with a bromobutyl side chain 17 showed antimalarial activity against both a chloroquine sensitive and resistant strains of Plasmodium falciparum with IC50 values of 3.7 and 4.0 µg/mL, respectively. None of the bisquaternary pyridinium compounds showed antimicrobial, or antiprotozoal activity. None of the compounds showed cytotoxic effects towards mammalian kidney fibroblasts. Results of this study indicate that the pyridinium compounds, some of which are already in use as antidotes, do not have significant antimicrobial and antiprotozoal activities and cannot be relied upon for additional protection in the event of combined chemical-biological incident.

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Section: Methodsmentioning

confidence: 99%

Antimicrobial, Antimalarial, and Antileishmanial Activities of Mono‐ and Bis‐quaternary Pyridinium Compounds

Bharate

Thompson

2010

Chem Biol Drug Des

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“…[22] We reported N,N'-hexamethyleneA C H T U N G T R E N N U N G [bis(4-carbamoyl-1-octylpyridinium)] dibromide (PAM-86: 5), a potent antimalarial compound that can be synthesized inexpensively by using isonicotinic acid (11) as a starting material ( Figure 1). [23] Although the in vitro antimalarial activity of PAM-86 (5) was found to be as potent as that of chloroquine (1) (IC 50 was 10 nm when the FCR-3 strain was used as a malarial plasmodium), [23] the in vivo activity in mice was less potent than that of chloroquine (1) (unpublished data). In addition, it was difficult to modify the side-chain structure.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…The first lead compounds, PAM-86 (Figure 7), exhibited promising antiplasmodial activities in vitro (IC 50 = 10 nm), but not in vivo. [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.…”

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confidence: 99%

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

et al. 2011

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For more than 50 years dequalinium chloride has been used successfully as an antiseptic drug and disinfectant, particularly for clinical purposes. Given the success of dequalinium chloride, several series of mono- and bisquaternary ammonium compounds have been designed and reported to have improved antimicrobial activity. Furthermore, many of them exhibit high activity against mycobacteria and protozoa, especially against plasmodia. This review discusses the structure-activity relationships and the modes of action of the various series of (bis)quaternary ammonium compounds.

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Antimalarial effect of bis-pyridinium salts, N,N′-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

Cited by 35 publications

References 5 publications

Antimicrobial, Antimalarial, and Antileishmanial Activities of Mono‐ and Bis‐quaternary Pyridinium Compounds

Antimicrobial, Antimalarial, and Antileishmanial Activities of Mono‐ and Bis‐quaternary Pyridinium Compounds

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

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

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