Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum

Abstract

Robenidine is a veterinary drug used in the poultry industry to treat coccidiosis caused by parasites in the Eimeria genus. Though this compound and related aminoguanidines have recently been studied in other pathogens, the chemotype has not been systematically explored to optimize antimalarial activity despite the close genetic relationship between Eimeria and Plasmodium (both are members of the Apicomplexa phylum of unicellular, spore-forming parasites). In this study, a series of aminoguanidine robenidine analogues was prepared and tested in vitro against Plasmodium falciparum , including multidrug-resistant strains. Selected compounds were further evaluated in vivo against murine Plasmodium yoelii in mice. Iterative structure–activity relationship studies led to the discovery of 1 , an aminoguanidine with excellent activity against drug-resistant malaria in vitro and impressive in vivo efficacy with an ED 50 value of 0.25 mg/kg/day in a standard 4-day test.

Mononuclear/Binuclear [VIVO]/[VVO2] Complexes Derived from 1,3-Diaminoguanidine and Their Catalytic Application for the Oxidation of Benzoin via Oxygen Atom Transfer

“…Robenzidene, popularly known as “ Robenidine ,” is 1,3-diaminoguanidine-derived N′, 2-bis­(€-4-chlorobenzylidene)­hydrazine-1-carboximidhydrazide hydrochloride and was possibly the first compound developed as a poultry anticoccidial agent in the early 1970s. This was later extended to the whole range of apicomplexan parasites causing the disease coccidiosis in other smaller cattle such as dog, cat, sheep, goat, and so forth. − Very recently, Krollenbrock et al have prepared Robenidine analogues having different substituents on the benzaldehyde moiety and tested them as potential antimalarial drugs in vitro as well as in vivo against Plasmodium falciparum, including multidrug-resistant strains . Over the years, modified Robenidine analogues have also been prepared by several groups and screened for anti-inflammatory activities .…”

“… 1 − 7 Very recently, Krollenbrock et al have prepared Robenidine analogues having different substituents on the benzaldehyde moiety and tested them as potential antimalarial drugs in vitro as well as in vivo against Plasmodium falciparum , including multidrug-resistant strains. 8 Over the years, modified Robenidine analogues have also been prepared by several groups and screened for anti-inflammatory activities. 9 Other areas where such compounds find applications are colorimetric determination of fluoride, 10 chemo sensor for Hg(II) ions, 11 fluorescent detection of Zn(II) ions, 11 and fluorometric determination of microgram level of gallium in biological tissues.…”

Isopropoxy Benzene Guanidine Ameliorates Streptococcus suis Infection In Vivo and In Vitro

“…Robenidine is widely used in the treatment of coccidial infections in poultry and rabbits, and its antimicrobial efficacy was later evaluated when it was found to be more effective against Gram-positive bacteria, S. pseudintermedius and beta-hemolysis streptococcs, and showed good synergistic effects when used in combination with EDTA against Gram-negative bacteria [ 49 ]. In the structure-activity relationship (SAR) investigation of robenidine, it was found that the antibacterial activity of the 4-OH robenidine analog was significantly reduced, and its methylated analog (4-OCH 3 ) had no antibacterial activity, in contrast, whereas the alkyl substituent analog was more effective, with 4-CH 3 and 4-CH(CH 3 ) 2 being more prominent [ 50 , 51 ]. This shows that 4-OCH(CH 3 ) 2 is essential for the antibacterial activity of IBG.…”

Design, synthesis, molecular docking and biological evaluation of 1,2,4-triazole derivatives possessing a hydrazone moiety as anti-breast cancer agents

“…These compounds were synthesized according to the modified literature procedure: 42 acetophenones ( 1 ) (1 g, 8.32 mmol, 1 equiv.) and 1,3 diaminoguanidine hydrochloride ( 2 ) (0.52 g, 4.16 mmol, 0.5 equiv.)…”