Schistosomicidal activity

This ring system was prepared by treatment of quinoline derivative 786 with antimonyl chloride to give 787. Quinoline derivative 786 was prepared by Mannich reaction on 2,8-dihydroxylepidine with diethylamine and formaldehyde to afford the respective diethylaminomethyl derivative that followed by subsequent nitration. The schistosomicidal activity of 787 was studied (80MI66) (Scheme 138). 

Many papers deal with both analytical determination and cathodic transformations of thiones (21). Thus, a four-electron reduction of OLTIPRAZ [4-methyl-5-(2-pyrazinyl)-l,2-dithiole-3-thione] produces several species that could account for the schistosomicidal activity of metabolites of the starting compound. The first two-electron reduction (in aqueous media) affords the scission of the S —S linkage and the thus formed dianion can be readily [197] alkylated by common alkyl halides. Let us note that the cathodic behavior of structure (21) was shown to be strongly influenced by the nature of substituents and particularly [198] by the electron-donating ability of Rh... 

Substituted azojuracils — The coupling of 5-diazouracil (XXXIX) with certain aminonaphthalene derivatives yielded a number of 5-(4-substituted amino-l-naphthylazo)uracils (XL) which exhibit high schistosomicidal activity against Schistosoma mansoni [334—336]. Compounds of this type were selected from among 500 azo-substituted-heterocyclic compounds after extensive studies in experimental animals [334]. 

Many 3-dialkylaminomethyl- and 5-dialkylaminoalkylaminothio-chroman-4-ones exhibit schistosomicidal activity,and a variety of other aminothiochromans are antiamebic. " The thiochroman ring is also found in antimicrobial agents,virucides, insecticides, and acaricides, and antiedemic and anti-inflammatory agents. Hexahydrothiochroman has been employed as a fuel additive, and several <-butyl thiochroman-4-ones have been studied for their... 

A few nitrothiophenes have been shown to possess marked schistosomicidal activity, though weaker than nitrofurans or nitrothiazoles. Of these, compounds 9 and 10 exhibited potent activity. Compound 9, which bears a close resemblance with furapyrimidone, caused 100% elimination of S. mansoni from mice at a dose of 250 mg/kg [19], while 10 was found to be active against S. mansoni, S. japoniaim and S. haematobium infections in experimental animals and also proved to be less toxic in dogs and cebus monkeys [20a]. Alaimo and Hatton [20b] have prepared a... 

The compounds belonging to class 7a,b and 8a,b were evaluated for their schistosomicidal activity against S. mansoni in mice and monkeys [19,20], In general, compounds derived from 2-aminomethyl-l,2,3,4-tetrahydroquinoline (7a,b) as well as 2,3,4,4a,5,6-hexahydro-lH-pyrazino[l,2-a]quinohne (8a,b) exhibited high schistosomicidal activity in experimental animals however, promising activity was observed in 2-(N,N-dialkylaminomethyl)-l,2,3,4-tetrahydroquinolines (9) [12,17,21],... 

The SAR studies carried out in 9 indicated that high schistosomicidal activity is obtained when an electron withdrawing group is present at 7-position only. The activity order as consequence of the substitution at 7-position in 9 was N02>CN>F>Cl>Br, This is in direct contrast with the mirasan series, where this activity order is reversed (halogen>CN>N02), These results may be explained in terms of lipophilicity [17],... 

The presence of the methyl group at 6-position in 9 was equally important for schistosomicidal activity as the 6-desmethyl and 6-ethyl analogues (10a,b) were found to be inactive. In addition, introduction of aromaticity in the piperidine part of 9 (eg, 11), substitution at 1-position or extension of the chain length at 2-position (12) resulted either in lowering or loss of schistosomicidal activity [12],... 

Potential Chemotherapeutic Agents - The microbial transformation of lucanthone by As rgillus sclerotlorum to give the hydroxymethyl conqpound, hycanthone (XlXb), the active metabolite, has been described.9 Similar microbial metabolism of some N-substituted 3-chloro-jB,-toluidines (XXa) to the corresponding 4-hydroxymethyl derivatives (XXb) resulted in enhanced Schistosomicidal activity in mice and hamsters.9 toco iraging clinical... 

The outstanding compound to show schistosomicidal activity in a series of 5-aniinoquinolines was RD 12,80 [6-chloro-5-(2-diethylamino-ethyleunino )-8-methylq.uinoline ] (XXIl).° Against mansoni in mice the compound was active at 30 mg/kg. RD 12,869 was reported to be effective in Cebus monkeys as well as in mice against mansoni, but ineffective... 

In several classes of compounds the schistosomicidal activity depends on a -substitution of a methyl group and a basic side chain. 

Gonnert warned that "the above conclusions as to the structure-activity relationships are based on the presumption that the compounds themselves and not one of their metabolites are responsible for the schistosomicidal activity". Strufe tried to identify the active metabolite of Uiracil D but was not successful. Despite Strufe s failure, the notion persisted that the schistosomicidal activity of Miracil D was mediated through one of its metabolites. Why should the 6-chloro analog of Miracil D be about three times as active in the mouse, yet be totally inactive in the monkey Why should Miracil D itself be much more active in the monkey, the species in which the metabolism is most extensive ... 

The hydroxylated compound VI was easily detected in the urine of mice medicated with V, but despite a careful search in urine of monkeys similarly treated, we were unable to find VI even in trace amounts. The conversion product VI is much less active as a schistosomicidal agent than hycanthone in hamsters the apparently greater activity of V in mice as compared with Miracil D is a result of more efficient enzymatic hydroxylation rather than of its intrinsic schistosomicidal activity. 

Do all tri-cyclic congeners of Miracil D have to be activated by hydroxylation of the 4-methyl group We answered this question in an indirect, but much less time-consuming manner. We prepared a series of hydroxylated analogs of hycanthone and compared their schistosomicidal activities in hamsters with that of their precursors, as shown in Table II. 

Regardless of the type of substitution replacement of the 6-H by 6-Cl (II-2), replacement of S by 0 (II-3), reduction of ring A (II-4), oxidation of S to SO (II-5) or change in the side-chain (II-6), the hydroxylated metabolite is the more active compound. We take this as strong, if not conclusive evidence, that in this series metabolic activation is a general requirement for schistosomicidal activity. 

Schistosomicidal Activity in Hamsters of a Series of Congeners of Miracil D and Hycanthone... 

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