Structure−Activity Study of Pentamidine Analogues as Antiprotozoal Agents

Abstract

Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.

Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues

“…17 The di-nitriles 14a–b were converted to the diamidines 15a–b using LiN[TMS] 2 as previously mentioned.…”

Pharmacophore model for pentamidine analogs active against Plasmodium falciparum

“…1), which have terminal amidines and two phenyl rings connected by a 5-membered aliphatic chain (for details on synthesis see Bakunova et al [23]). In vitro antimalarial activity was tested in quadruplicates to obtain high-quality IC 50 data for the modeling.…”

facile, highly efficient and novel method for synthesis of 5-substituted 1H-tetrazoles catalysed by copper(I) chloride

“…Various methods have been reported for the synthesis of 5-substituted 1H-tetrazoles, most of which are based on the addition of the nitrile group of sodium azide (NaN 3 ) and trimethylsilyl azide (TMSN 3 ). These reactions were carried out using catalysts such as Fe(OAc) 2 (Bonnamour & Bolm, 2009), Brønsted acid catalyst (Bakunova et al, 2009), AlCl 3 (Matthews et al, 2000).…”