Based on the antimalarial properties observed for 2-acetylpyridine 4-phenyl-3-thiosemicarbazone (1), an extensive series of related thiosemicarbazones was prepared and tested against Plasmodium berghei in mice. Screening results indicated that the presence of the 2-pyridylethylidene group was critical and that certain phenyl, benzyl, phenethyl, or cycloalkyl groups at N4 of the thiosemicarbazone moiety also contribute to antimalarial activity.

No abstract

Reaction of the 2-acetylpyridine thiosemicarbazones, 3-azabicyclo[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IIIa), its selenium analogue (IIIb), 1H-hexahydroazepine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IV), and 1H-octahydroazocine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (V) with Cu(II), Ni(II), Fe(III), and Mn(II) salts gave crystalline complexes. Relative to the free ligands, these complexes show reduced antimalarial activity in mice infected with Plasmodium berghei; however, antileukemic properties are enhanced by coordination with the above-mentioned metals.

Reduction of the azomethine bond of 2-acetylpyridine thio- and selenosemicarbazones with sodium borohydride readily afforded the corresponding thio- or selenosemicarbazides when they were N4,N4-disubstituted. This conversion failed, however, when the thio- or selenosemicarbazones were N4-substituted or unsubstituted. A more general route to the desired thio- or selenosemicarbazides consisted of reduction with sodium borohydride of methyl 3-[1-(2-pyridyl)ethylidene]hydrazinecarbodithioate to give the 2-pyridylethyl derivative. Displacement of methyl mercaptan from the thio ester moiety of the latter by amines produced 1-[1-(2-pyridyl)ethyl]-3-thiosemicarbazides. These compounds were somewhat more active as antimalarial agents in Plasmodium berghei infected mice than the corresponding thiosemicarbazones; however, the enhancement of activity was accompanied by an increase in toxicity. Compound 7, 3-azabicyclo[3.2.2]nonane-3-carbothioic acid 2-[1-(2-pyridyl)ethyl]hydrazide, is the most potent derivative of 2-acetylpyridine we have evaluated to date.

New drugs and molecular targets are needed against Trypanosoma brucei, the protozoan that causes African sleeping sickness. Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), a traditional antifungal agent, and 11 analogs were tested against T. brucei in vitro. The greatest activity was conferred by electron-withdrawing groups in the 8 position of the tryptanthrin ring system; the most potent compound had a 50% effective concentration of 0.40 M.Members of the Trypanosoma brucei species are flagellated protozoa that are transmitted by tsetse flies. They cause sleeping sickness in humans and a related disease in cattle. The characteristic meningoencephalitis of African sleeping sickness is fatal if it is not treated, and currently available drugs are limited by toxicity and growing parasite resistance (7,9,12). Unfortunately, in recent years there has been a dramatic and devastating resurgence of sleeping sickness (14). The need for safe and effective new antitrypanosomal agents is pressing.Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione; in Fig. 1, X is H in tryptanthrin) is a weakly basic alkaloid found in a number of plant species (11). This alkaloid is unusual in that its synthesis was described a half century before it was discovered as a natural product (6). Tryptanthrin is the active principal of a traditional Japanese herbal remedy for fungal infections (8). Subsequent studies extended the spectrum of antimicrobial activity to include bacteria (10, 11), particularly Mycobacterium tuberculosis (1). The activity of tryptanthrin against this intracellular organism prompted us to evaluate tryptanthrin and a series of derivatives of tryptanthrin against intracellular parasites, including Plasmodium falciparum, which causes malaria (13). In this report we describe the activities of a series of substituted tryptanthrins and 4-azatryptanthrins (Fig. 1) against Trypanosoma brucei, an extracellular protozoan parasite.Tryptanthrins. Tryptanthrin compounds were synthesized as described by Baker and Mitscher (1) and were characterized by their infrared and mass spectra. Stock solutions were prepared in dimethyl sulfoxide (99.8%; 27,685-5; Aldrich) and were then serially diluted into culture medium.Assay. Bloodstream-form T. brucei (MiTat 1.2, strain 427) organisms were grown axenically (5) at 37°C in HEPES-buffered Iscove's modified Dulbecco's medium that did not contain phenol red but that was supplemented with glutamate, hypoxanthine, cysteine, thymidine, sodium pyruvate, mercaptoethanol, bathocuproinedisulfonate, 10% Serum Plus, and 10% heat-inactivated fetal bovine serum, as described previously (2). Ten concentrations of each tryptanthrin were assayed in quadruplicate. Exponentially growing cells were incubated in 96-well plates (Falcon no. 3072 plates; Becton Dickinson) with or without test compound for 20 h and were then lysed and incubated for 3 to 6 h with p-nitrophenol phosphate. The acid phosphatase activity was determined, and 50% effective concentrations (EC 50 s) were obtained from curves fit to the da...