Antimalarial agents

Of industrial significance are ethyl 4,4,4-trifluoroacetoacetate [372-31-6] methyl 4,4,4-trifluoroacetoacetate, and isopropyl 4,4,4-trifluoroacetoacetate for the production of herbicides (eg, Monsanto s Dimension) and antimalarial agents such as Roche s Mefloquin [51773-92-3] as weU as ethyl 4,4,4-trichloroacetoacetate [3702-98-5] for the production of pharmaceuticals. 

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

The hydroxyl group is then replaced by chlorine by means of phosphorus oxychloride (70). Displacement of the reactive halogen at the 4 position by means of the aliphatic diamine, 71, yields the synthetic antimalarial agent chloroquine (72). ... 

The key intermediate for the preparation of the 8-aminoquin-oline antimalarial agents is obtained by condensation of the substituted aniline, 90, with "dynamite-grade" glycerol in concentrated sulfuric acid. (The reaction may well follow some scheme such as that depicted below.) Ihe nitroquinoline obtained from... 

Quinine hydrochloride [Fig. 22(c)], an antimalarial agent, acts primarily as a schizonto-cide, affecting sporozoites or preerythrocytic forms of malarial parasites [43]. Figure 23(c) shows potential oscillation with ImM quinine hydrochloride [21]. Fb.sds became very... 

Quantum chemistry, 11 (1975) 67 Quinolines, 8-amino-, as antimalarial agents, 28 (1991) 1... 

Coccidiosis is an economically significant respiratory disease of fowl. During the course of studies directed toward antimalarial agents, sulfani-tran (143) was prepared and found to be a coccidiostat. It is prepared conveniently by reaction of p-aceto-amidobenzenesulfonyl chloride with p-nitroaniline in acetic acid.68... 

Acridine dyes such as the antimalarial agent quinacrine (Atabrine) shown next are large planar aromatic compounds that intercalate or sandwich themselves between the stacked bases of the helix. 

Sastry et al. [42] reported the use of an extractive spectrophotometric method for the determination of primaquine and other antimalarial agents using Fast Green FCF (C.I. Food Green 3) or Orange II (C.I. Acid Orange 7). Sample solution... 

Ibrahim et al. [49] described a spectrophotometric method for the determination of primaquine and other antimalarial agents in pharmaceuticals. Powdered tablet or ampule contents containing 25 mg of primaquine phosphate, was dissolved in water and the solution was made alkaline with 6 M ammonia before extraction with chloroform. The extract was evaporated to dryness and the residue was dissolved in acetonitrile. A portion of the solution was mixed with 0.04% tetracyanoethylene solution in acetonitrile and diluted to volume with acetonitrile. After 10 min, the absorbance was measured at 415 nm for primaquine. Beer s law was obeyed from 2 to 12 mg/mL. The results agreed well with those of the United State Pharmacopoeia XX method. 

Dwivedi et al. used a thin-layer chromatographic densitometric and ultraviolet spectrophotometric methods for the simultaneous determination of primaquine and a new antimalarial agent, CDRI compound number 80/53 [68]. The new antimalari-al agent, compound 80/53 is unstable in acidic conditions where it is converted into primaquine. To conduct stability studies of this compound, thin-layer chromatography densitometric and ultraviolet spectrophotometric determination methods were developed. These methods are also suitable of the determination of compound 80/53 or primaquine in bulk and pharmaceutical dosage forms. 

Moore and Hemmens [119] studied the photosensitization of primaquine and other antimalarial agents. The drugs were tested for in vitro photosensitizing capability by irradiation with 365 nm ultraviolet light in aqueous solutions. The ability of these compounds to photosensitize the oxidation of 2,5-dimethylfuran, histidine, trypotophan, or xanthine, and to initiate the free radical polymerization of acrylamide was examined in the pH range 2 12. Primaquine does not have significant photochemical activity in aqueous solution. 

Olenick [152] presented a review on primaquine. Fernex and Leimer [153] reviewed the pharmacology and clinical properties of primaquine and other antimalarial agents. 

Alkaloids 39 and 40, which are enantiomers of one another and are both used as antimalarial agents, inhibited GST Pl-1 in the single-digit micromolar range (IC50 = 4 and 1 pM, respectively), indicating that the chirality of the secondary alcohol does not play a significant role in this activity. Pyrimethamine (41),... 

Fig. 14. X-ray crystal structure of [Ga(madd)]+ 80, a potential antimalarial agent. Adapted from (343).

A two-step transformation of conjugated dienes into non-conjugated ones was proposed for the synthesis of the difficult to-obtain lapachol (355) (a member of a class of antimalarial agents having an activity against the Walker carcinosarcoma 256) from the more available isolapachol 352183. This method consists in an oxidative cyclization of isolapachol 352 by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to form a mixture of the products 353 and 354 (equation 127). Treatment of this mixture with dilute acid in... 

Chen M, Theander TG Christensen SB, Hviid L, Zhai L, Kharazmi A. (1994) Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii mitctxon. Antimicrob Agents Chemother 38 1470-1475. 

Diethyl aminomalonate reacts with 1,3-diketones in boiling acetic acid to the corresponding pyrrolecarboxylates 11 (87JOC3986). From N-ac t-amidomalonate and acroleins, pyrrolidines were prepared and they were further transformed into functionalized pyrroles, which are a part of the antibiotic lyncomycin and an antimalarial agent (67JA2459 72JMC1255). 

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