Pharmaceuticals antimalarials

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. 

Mourier s report was quickly followed by successful enantiomeric resolutions on stationary phases bearing other types of chiral selectors, including native and deriva-tized cyclodextrins and derivatized polysaccharides. Many chiral compounds of pharmaceutical interest have now been resolved by packed column SFC, including antimalarials, (3-blockers, and antivirals. A summary is provided in Table 12-2. Most of the applications have utilized modified CO, as the eluent. 

Abdel-Salam et al. [21] described a sensitive and simple spectrophotometric method for the determination of primaquine and other antimalarial drugs. The method is based on the formation of complexes between iodine (as an acceptor) and the basic drug in chloroform solution. Optimum conditions were established for the determination of primaquine, in pure form or in pharmaceutical preparation. Results were accurate and precise. 

Sastry et al. [41] used a new spectrophotometric method for the estimation of primaquine, using 3-methylbenzothiazolin-2-one hydrazone. An aqueous extract of the sample of powdered tablets (containing 50 pg/mL of primaquine phosphate was mixed with 1 mL each of aqueous 8.5 mM 3-methylbenzothiazolin-2-one hydrazone and 11.84 mM CelV (in 0.72 M sulfuric acid), the mixture was diluted to 10 mL, and the absorbance was measured at 510 nm versus a reagent blank. Beer s law was obeyed for 0.7-12 pg/mL of the drug and for 50 pg, the coefficient of variation was 0.52%i (n = 8). Other antimalarials and pharmaceutical adjuvants did not interfere. 

Mahrous et al. [43] determined primaquine and other antimalarials by use of chloranilic acid for the colorimetry. Primaquine was treated with 0.2 chloranilic acid solution in acetonitrile to give a purple solution with absorption maximum at 522 nm. Beer s law was obeyed from 0.04 to 0.2 mg/mL. Analysis of pharmaceutical formulation by this method is as accurate as the official method. 

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. 

Hassan et al [65] used a method for the determination of primaquine and other antimalarials, through ternary complex formation. The analytical aspects of the reaction between the widely used antimalarial drugs with cobalt and thiocyanate to form ternary complexes are described. Alternatively, determination of the cobalt content of the nitrobenzene extract using atomic absorption spectroscopy provided an indirect method for the determination of the drugs. Both methods are applied to the analysis of pharmaceutical preparation and the results obtained agreed well with those obtained with official methods. 

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. 

Li GQ. (1989) Clinical studies on artemisinin suppository and on artesunate and artemether. In S. Jiaxiang (ed.), Antimalarial drug development in China. National Institute of Pharmaceutical Research and Development, Beijing, People s Republic of China, pp. 69-73. 

Since the first series of compounds were poorly soluble in water, the next crucial phase of the project set out to increase the water solubility of the drug candidates in order to increase absorption from the gastrointestinal tract. Further refinements led to a candidate that was not only well absorbed when administered orally to animals, but also had outstanding antimalarial profiles both in vitro and in vivo. In comparison to available semi-synthetic artemisinins, the drug candidate OZ 277 (Scheme 27) exhibits structural simplicity, an economically feasible and scalable synthesis, superior antimalarial activity and an improved pharmaceutical profile. The toxicological profiles are also acceptable and this drug candidate entered first into man studies during 2004. 

Other examples of pyrimidine-based pharmaceuticals include busipirone 1130, used to treat anxiety disorders, piribedil 1131 used for Parkinson s disease, epirizole 1132, a nonsteroidal antinflammatory (NSAID), pyrimethamine 1133, an antimalarial, minoxidil 1134, which is used for treating alopecia (male baldness), primidone 1135, which is used as an antiepileptic agent, and pyrantel pamoate 1136, which is used as an antiparasitic. 

Source Data from Agharkar, S., S. Lindenbaum, and T. Higuchi. (1976). Enhancement of solubility of drug salts by hydrophilic counterions Properties of organic salts of an antimalarial driJgPharm. Sci. 65 747-749. Copyright 1976 American Pharmaceutical Association, and reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley Sons, Inc. 

Stella V., J. Haslam, N. Yata, H. Okada, and S. Lindebaum. 1978. Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with oleic acid in a soft gelatin capdabamal of Pharmaceutical Sciences, 67(10) 1375-1377. 

CDD Collaborative Drug Discovery Repository of small-molecule libraries of more than 300,000 compounds derived from patents, literature, and high-throughput screening data shared by academic and pharmaceutical laboratories tested against M. tuberculosis preliminary public antimalarial database from multiple sources on 30,000 public compounds (https //www.collaborativedrug.com/pages/public access)... 

A separate vein of examples worthy of investigation can be found in a surprising location - pharmaceutical chemistry. In fact, this field abounds with aminoalkyl aromatic systems of varied structure. At least one reason for this wealth is that biogenic amines are of this structural type and serve as a continuing inspiration for the drug discovery effort. An early example is (43), first described in 1951 as a prospective antimalarial [101]. (43) has been found in our laboratory to display pH sensitive fluorescence [102] as expected of a PET sensor. The spacer of three carbon atoms limits the PET rate in the proton-free form which leads to a modest but useful proton-induced fluorescence enhancement. The fluorescence properties of another antimalarial (44) with structural features required of a PET sensor have been recently reported in a different context [103] and deserves sensory evaluation. 

N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates and of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monograph292. Hence, no further details are given here. 

Scheme 52 Pharmaceutical model accounting for the antimalarial activity...

Avery MA, McLean G, Edwards G, Ager A. Structure-activity relationships of peroxide-based artemisinin antimalarials. In Biologically Active Natural Products Pharmaceuticals. Cutler SI, Cutler HG, eds. 2000. CRC Press, Boca Raton, EL, pp. 121-132. Pareek A, Nandy A, Kochar D, Patel KH, Mishra SK, Mathur PC. Efficacy and safety of f -arteether and a/f -arteether for treatment of acute Plasmodium falciparum malaria. Am. J. Trop. Med. 2006 75 139-142. http //mednet3.who.int/EMUb/. 

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