In Vitro and In Vivo Antimalarial Activities of T-2307, a Novel Arylamidine

Abstract

bT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated the in vitro and in vivo antimalarial activity of T-2307. The 50% inhibitory concentrations (IC 50 s) of T-2307 against Plasmodium falciparum FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibited in vitro and in vivo antimalarial activity. M alaria, caused by protozoan parasites of the genus Plasmodium, is one of the world's leading killer infectious diseases. There are an estimated 200 to 300 million new cases of the disease each year worldwide, and 0.8 to 1 million deaths (5, 15). Many of these deaths occur in children and are the result of severe and cerebral malaria caused by Plasmodium falciparum, the most pathogenic of the four species that infect humans (5).In the absence of a vaccine for malaria and in view of widespread resistance of the parasites to antimalarial drugs in current use, new agents are urgently needed to combat malaria (4).We had previously reported that T-2307, a novel arylamidine, exhibits broad-spectrum in vitro and in vivo antifungal activity against clinically significant pathogens (7, 8, 16). The analogous arylamidine derivatives, such as pentamidine and DB75, exhibit antiprotozoan activities against Plasmodium, Trypanosoma, and Leishmania (2,3,14). Accordingly, T-2307, similar to pentamidine and DB75, is expected to exhibit antiprotozoan activity. In the present study, we investigated the in vitro and in vivo antimalarial activity of T-2307.The in vitro antimalarial activity of T-2307 against P. falciparum was examined. Parasite cultures were maintained in human erythrocytes suspended at 5% hematocrit in RPMI 1640 containing 0.5% AlbuMAX I solution and 5.95 g of HEPES, 2 g of NaHCO 3 , 0.5 g of L-glutamine, and 50 mg of hypoxanthine per liter. After the parasites had been synchronized to the ring stage by sorbitol lysis (6), T-2307 and reference agents were added to the synchronized parasite culture (ring stage, Ͼ90%, and parasitemia, 0.5%) in a 96-well plate. The plate was incubated for one intraerythrocytic life cycle (FCR-3, 40 h, and K-1, 48 h) at 37°C under a gas mixture of 5% O 2 and 5% CO 2 . In order to assess parasite growth, lysis buffer containing 0.02% SYBR green I was added to the parasite culture, and after incubation for 1 h, fluorescence was measured at excitation and emission wavelengths of 485 and 535 nm, respectively (12). The 50% inhibitory concentrations (IC 50 s) of T-2307 and the reference agents against the chloroquine-sensitive P. falciparum FCR-3 strain and the chloroquine-resistant P. falciparum K-1 strain are shown in Table 1. The IC 50 s of T-2307 against FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively, indicating that T-2307 exhibited no cross-resistance against chloroquine.The stage-specific activities of T-2307 and pentami...

Synthesis and Antifungal Activity of Benzamidine Derivatives Carrying 1,2,3-Triazole Moieties

“…This situation urged us to find new compounds having agricultural antifungal activities. Amidine derivatives exhibit several significant bioactivities, such as antitumor [2], trypanocidal [3,4,5], antiprotozoan [6,7], anti-HIV [8], diuretic, anti-inflammatory, analgesic [9], antivirus, fungicidal and bactericidal [10,11,12,13] activities. Amidines can also be used in the synthesis of metallo-organic compounds [14].…”

Decarboxylative Palladium(II)‐Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation

“…[14] Additionally, sterically congested aryl carboxylic acids are often excellent substrates in palladium-catalyzed transformations as ortho-substituents are known to facilitate the decarboxylation process. [15] Compounds with the amidine motif are of considerable interest in drug discovery and have been indicated as potential agents for the treatment of Alzheimers disease, [16] malaria, [17] and as inhibitors of acid-sensing ion channels, [18] platelet aggregation [19] and serine proteases. [20] Amidines are also useful precursors for the synthesis of a wide variety of heterocyclic ring systems such as quinazolines, [21,22] quinazolinones, [23] pyrimidines, [24,25] triazoles, [26] and benzimidazoles.…”

Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

“…The other MMV molecules identi ed as PfGAP50 binders are pending approval as drugs (SI_2). Although Me oquine, Suramin, Rifampicin, and Pentamidine were identi ed as binders to PfGAP50, their discontinued use against malaria [6][7][8] led us not to subject them for detailed in vitro stage-speci c and IMC inhibition assays. Among 11 molecules from C. pareira (SI-1_Fig 2), Hayatinine, Curine, and Magnocurarine were identi ed as PfGAP50 binders with KD below 100 µM (SI-1_Table-2).…”