Antimalarial activity in vitro

Blackie, M.A.L., Beagley, P., Chibale, K., Clarkson, C., Moss, J.R. and Smith, P.J. (2003) Synthesis and antimalarial activity in vitro of new heterobimetallic complexes Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines. Journal of Organometallic Chemistry, 688(1-2), 144-152. 

Biot C, Glorian G, Maciejewski LA, Brocard JS (1997) Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue. J Med Chem 40 3715-3718... 

To inspect the effect of the segment of 0-0-C-0-C-0-C=0 in the artemisinin molecule, carbaartemisinin 141 and its analogs 142-144 (Structure 5-18) were synthesized and evaluated. These compounds displayed much lower antimalarial activity in vitro than artemisinin. ... 

Most of the 16-functionalized fluoroartemisinins exhibited strong antimalarial activity in vitro (see Table 6.7) and in vivo (see Table 6.8) [46, 57], Only the diester 23q and the diacid 23r were found to be inactive against Plasmodium falciparum. The more promising... 

Marine isonitriles have recently inspired the synthesis of some analogues that showed good antimalarial activity in vitro [39, 40]. Among them, a series of easily accessible synthetic isonitriles [e.g. 26-29, Fig. (5)] have also been tested in vivo against the multi-drug resistant Plasmodium yoelii. Compound 29 showed a good activity, although its therapeutic index is poor. 

Desjardin R E, Canfield C J, Haynes J D, et al. (1979). Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 16 710-718. 

Some chiral metabolites of antimalarial drugs possess significant levels of antimalarial activity in comparison to parent drug. For example, the main circulating metabolite of halofantrine, ( )-desbutylhalofantrine, possesses an in vitro level of antimalarial activity similar to that of parent drug [42]. The enantiomers of this metabolite also share similar antimalarial activities in vitro. Stereoselectivity in pharmacokinetic properties of these chiral metabolites could influence an assessment of antimalarial activities. On the other hand, neither of the enantiomers of the major 4-carboxylic acid metabolite of mefloquine possesses antimalarial activity [43]. 

Wright, A.D. and Lang-Unasch, N. (2009) Diterpene formamides from the tropical marine sponge Cymbastela hooperi and their antimalarial activity in vitro. J. Nat. Prod., 72, 492-495. 

In 1993, the effects of selected topoisomerase II inhibitors, antimalarial agents, DNA binders, naphthoquinones, and various other agents on integrase activity in vitro were investigated [46]. 

In order to exploit the antimalarial activity of CQ, coordination of CQ by different metals has been explored. The triphenylphosphinegold(I)-CQ complex (Fig. 7) was found to have a ninefold higher activity in vitro than CQ against FcBl and FcB2 Colombian CQ-resistant strains of P. falciparum. The complexation of Au to CQ also increased the in vivo susceptibility of P. berghei to CQ [95]. 

Torok et al. reported that the reaction of artemisinin and methanolic ammonia or primary alkyl-and heteroaromatic amines yielded azaartemisinin or A-substituted azaartemisinin (137) and A-substimted azadesoxyartemisinin (138) as byproducts (Scheme 5-22). Some A-substimted azaartemisinin had good antimalarial activity, such as compound 137 (R = CH2CHO), which was 26 times more active in vitro and 4 times more active in vivo than artemisinin. ... 

Kristensen S, Wang RH, Tonnesen HH, Dblon J, Roberts JE. Photoreactivity of biologicaUy active compounds. VIII. Photosensitized polymerization of lens proteins by antimalarial drugs in vitro. Photochem Photobiol 1995 61 124—130. 

The subtle chemistry of difluoroenoxysilanes has not been fruitful in our search for new antimalarial drug candidates. All our attempts to convert ketones 21 into acids failed (Baeyer-Villiger reaction, oxidation of the aryl moiety). Furthermore, the configuration at C-9 in artemisinins is known to be crucial for the antimalarial activity [5], Ketones 21 are much less active in vitro and in vivo than artemether. 

Berberine chloride was evaluated for antimalarial activity against Plasmodium falciparum in vitro (two clones of human malaria Plasmodium falciparum D-6 [Sierra Leone clone] and W-2 (Indochina clone) and Plasmodium berghei in vivo (mice). The alkaloid exhibited an antimalarial potency equivalent to that of quinine in vitro, but was inactive in vivo. The results were consistent with those of others who have found berberine to be a potent inhibitor in vitro of both nucleic acid and protein biosynthesis in P. falciparum, and have demonstrated a strong interaction of berberine with DNA. In addition, the lack of in vivo antimalarial activity in mice observed with berberine and other protoberberine alkaloids agrees with clinical reports that have claimed berberine to be inactive as an antimalarial drug [228]. 

It is worth noting that the two optical isomers of ferroquine exist due to the planar chirality of the unsymmetrically 1,2-substituted ferrocene moiety. Both enantiomers were prepared by enzymatic resolution of an ester intermediate in >98% optical purity. Both isomers display similar activity in vitro " Although both enantiomers are less active than the racemate in vivo the (+)-enantiomer displays better curative effects than the optical antipode. This different behavior indicates different pharmacokinetics of the two enantiomers. Ferrocene derivatives of other antimalarial drugs like artemisinine, quinine, and mefloquine have also been tested, as well as various other chloroquine-derived organometallics. Moss and coworkers synthesized and tested chloroquine and ferroquine derivatives with other organometallic groups. 

O Neill MJ, Bray DH, Boardman P, Phillipson JD, Warhust DC, Peters W, Suffness M (1986) Plants as sources of antimalarial drugs in vitro antimalarial activities of some quassinoids. Antimicrob Agents Ch 30 101... 

Ferroquine has passed clinical phase II trials as an antimalarial drug. Both enantiomers of ferroquine are equally active in vitro. Explain why the molecule is chiral, and draw the structure of (S)-ferroquinone. 

Plants that contain protoberberine alkaloids are reported to be used as analgesics, antiseptics, sedatives, and stomatics in Chinese folk medicine. In Indian and Islamic folk medicine, such plants are used for bleeding disorders and eye diseases, and as antiseptics, sedatives, stomatics, and uterine muscle depressants. Both quaternary alkaloids and their tetrahydro derivatives possess many substantiated biological and therapeutic effects, e.g., pahnatine, jatrorrhizine, and tetrahydropahnatine have been reported to show in vitro antimalarial activity. In China, tetrahydropalmatine is used as an analgesic, and has been reported to exhibit bradycardial, hypotensive, and sedative activities 4). 

Chirata xanthones (swertianin, 1,3,7,8-tetra-hydroxyxanthone, and 1,8-dihydroxy-3,7-dimethoxyxanthone) are claimed to have antituberculous activities. Amarogentin has shown in vitro hepatoprotective activity against carbon tetrachloride toxicity. Swerchirin has shown antimalarial activity in vivo ... 

Volatile oils obtained from peppermint, corn-mint, and other mint species have antimicrobial, antimalarial and antigiradial activities in vitro. Peppermint extracts have been reported to have antiviral activities against Newcastle disease, herpes simplex, vaccinia, Sem-liki Forest, and West Nile viruses in egg and cell culture systems (see babn) The ethyl acetate extract of Moroccan M. longifolia was also found to possess inhibitory activity against HIV-1 reverse transcriptase. ... 

Trioxaquines have modular structures linking two different moieties. A study of the relation between the structure of the trioxaquines and their antiplasmodial activities in vitro and in vivo was done. All the trioxaquines tested in vitro present interesting antimalarial properties on strains of Plasmodium falciparum chloroquine-sensitive and chloroquine-resistant with ICso inferior to 100 nM and around 10 nM for the best trioxaquines 41). 

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

---