Synthesis and in Vitro Antiprotozoal Activities of Dicationic 3,5-Diphenylisoxazoles

Abstract

3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity) in vitro. Eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 values) at least 10 times higher than that of furamidine. Eighteen compounds (4-8, 12, 14, 18-22, 25, 26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC50 values less than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.

Synthesis, DNA binding, fluorescence measurements and antiparasitic activity of DAPI related diamidines

“…15 Oxidative cleavage of 6 using sodium periodate in tetrahydrofuran-water mixture afforded the aldehyde 7 15,16 Since the Ramirez olefination is sensitive to amine or amide functional groups, so we decided to start with the nitro compound 7 which we planned to reduce later. The dibromoalkene 8 was prepared efficiently with the Ramirez (Wittig-type) dibromoolefination of the corresponding aldehyde 7 using carbon tetrabromide as a reagent and triphenylphosphine as a catalyst.…”

“…Triphenylphosphine (7.9 g, 30 mmol) was added portionwise to an ice cold solution of 4-cyano-2-nitro-benzaldehyde 15,16 (7) (1.76 g, 10 mmol), carbon tetrabromide (5.0 g, 15 mmol) and zinc powder (0.65 g, 10 mmol) in anhydrous methylene chloride (100 mL), stirred overnight, filtered to remove triphenylphosphine oxide and zinc bromide, concentrated, purification by column chromatography on silica gel using hexanes/dichloromethane (70/30, v/v) …”

Structure-Based Drug Discovery for Tropical Diseases

“…A start point to tackle these issues is the molecular manipulation of known drugs or active classes of compound to generate new scaffolds with improved potency, safety or straightforward synthesis. Currently, analogues of existing antiparasitic drugs are under investigation for a variety of neglected diseases [28][29][30][31][32][33][34][35][36][37].…”

Reaction of β‐dimethylaminovinyl ketones with hydroxylamine: A simple and useful method for synthesis of 3‐ and 5‐substituted isoxazoles

“…Recently, these compounds have been found to be an integral part of the selective inhibitors of the transglutaminase human 2 being thus important prototypes for treatment of Huntington's, Alzheimer's, and Parkinson's diseases [2]. Other pharmacological activities of this core involve the potent and selective antagonism of NMDA receptor [3], antagonism of the GABA A receptor, in the low nanomolar range, [4] and in vitro antiprotozoal activities [5].…”