Blood schizontocidal activity

Methylprimaquine (45) is the first member of this class which was synthesized by Elderfield et al. in 1955 [54]. This compound was found to possess less toxicity and better radical curative and blood schizontocidal activity than primaquine in mice [72]. However, 4-methylprimaquine could not be taken up for drug development because of its high toxicity found in dogs and monkeys during detailed studies [75]. Attempts to improve the biological profiles of 45 led to the synthesis of a series of 4-substituted primaquines [76,77], of which 46-49 exhibited blood schizontocidal activities [44,45]. 

At a dose of 80 mg/kg, the vinyl (46) and ethyl (47) derivatives of primaquine exhibited weaker blood schizontocidal activity than primaquine. However, 47 was non-toxic at the doses ranging from 20-640 mg/kg and also produced 100% curative... 

Chen et al. [72] have prepared some 2,5-disubstituted derivatives of primaquine. The most notable activity was displayed by 2-methyl-5-( -hexyloxy- and ri-hexylthio)primaquines (57a,b). Both these compounds exhibited blood schizontocidal activity at a dose of 20 and 160 mg/kg, respectively [45]. Another series of 2,5-disubstituted primaquines, represented by the general formula 58, have been... 

WR-242511 (59) has been found to be curative at a dose of 2.5 mg/kg in the Rane screen. It also cured 5 of 5 monkeys treated at a dose of 0.1 mg/kg. Unfortunately WR-242511 produces worrisome methaemoglobinemia in dogs (48.1% as compared to 25.3% of WR-225448 and 16% for WR-238605) [96]. Nevertheless, this compound is considered as a candidate antimalarial because of its excellent radical curative and blood schizontocidal activities at dose levels of 0.1 and 20 mg/kg, respectively. WR-242511 is at present undergoing detailed preclinical studies [45]. 

Answer For a radical cure", patients are treated with a 14-day course of primaquine. It usually follows a course of chloroquine or other blood schizontocide. Primaquine is active against the exoerythrocytic forms of FL vivax. It is also strongly gametocidal against all four plasmodial species. 

Spathodea campanulata decoction of the leaves and stem bark is used for treating malaria. The leaf and stem bark extracts each demonstrated antiplasmodium activity in the early infection but less effective once infection is estabhshed (68,69,70). The antimalarial active principles in the stem bark are 3p-20-hydroxyurs-12-en-28-oic acid and two of its derivatives 3p- hydroxyurs-12,19-dien-28-oic acid (tomentosolic acid) and 3p,20p-dihyroxyurs-12-en-28-oic acid. The active principles each had significant blood schizontocidal actions in both the early and established infections (77). The stem bark also contains P-sitosterol (72).Other uses of Spathodea campanulata in traditional Swazi medicine which has been documented include the use of the bark, leaves and... 

Halofantrine is a potent blood schizontocidal agent with high activity against chloroquine-resistant and chloroquine-sensitive P, falciparum. The drug has been used at a dose of Ig/adult given daily for 3 days no phototoxicity or gastrointestinal problems were observed [138,139],... 

In general the 5-aryloxy analogues (51, X=0) of primaquine exhibited moderate to good activity in radical curative tests. The corresponding arylthio and ary-lamino derivatives (51, X=S,NH) were found to be nontoxic with poor or no activity upto a dose level of 640 mg/kg in the blood schizontocidal screen [45]. In the radical curative test, 5-aryloxy or 5-aiylthio derivatives of primaquine with a halogen exhib-... 

A few derivatives of primaquine carrying substituents at its 2- and 4-positions have been synthesized, but none showed promising therapeutic response [87]. Interestingly, compounds 56a-c were found to be less toxic than primaquine at the same time these were less active too than primaquine in the blood schizontocidal screen. However, primaquine and 56a possess equal activity as tissue schizontocides [45]. 

Disubstituted primaquine analogues exhibited broader spectrum of anti-malarial activities compounds 59-61 exhibited both blood schizontocidal (P. berghi in mice) and radical curative P.cynomolgi in rhesus monkeys) activities and were also less toxic [26,44,45]. 

WR-238605 (61), which is the 2-methoxy derivative of compound 60, has been shown to possess better blood schizontocidal and radical curative activities. It also produced less methaemoglubinemia (16% as compared to 25.3% of WR-225448) [97]. This compound also showed slightly better activity than WR-225448 against P. vivax in Aotus monkeys at a dose of 1 mg/kg for 3 days [45]. 

Some hexahydroderivatives of quinacrine have also been synthesized of which floxacrine (HOE-991, 31) exhibited causal prophylactic and blood schizontocidal ac-tiviy against drug- resistant strains of P. berghei, P. falciparum and P. vioax in experimental animals [37,38]. The imino analogue (32) of floxacrine has been found to possess even better activity than 31 [8,39,40). However, due to toxicity floxacrine and its analogues could not be used clinically. 

Warhurst, D. C. (1987). Antimalarial interaction with ferriprotoporphyrin IX monomer and its relationship to activity of the blood schizontocides. Ann. Trap. Med. Parasitol. 81,65-67. 

ANTIMALARIAL ACTIONS Mefloquine is a highly effective blood schizontocide but has no activity against early hepatic stages and mature gametocytes of P. falciparum or latent tissue forms of P. vivax. The drug may have some sporontoddal activity but is not used clinically for this purpose. 

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