Synthesis and Evaluation of Novel DNA Minor Groove Binders as Antiamoebic Agents

Abstract

The free-living amoeba Acanthamoeba castellanii is responsible for the central nervous infection granulomatous amoebic encephalitis and sight-threatening infection Acanthamoeba keratitis. Moreover, no effective treatment is currently present, and a combination drug therapy is used. In this study, twelve DNA minor groove binders (MGBs) were synthesized and tested for their antiamoebic activity via amoebicidal, encystation, excystation, and cytopathogenicity assays. It was found that the compounds MGB3, MGB6, MGB22, MGB24, and MGB16 significantly reduce amoeba viability to 76.20%, 59.45%, 66.5%, 39.32%, and 43.21%, respectively, in amoebicidal assays. Moreover, the compounds MGB6, MGB20, MGB22, MGB28, MGB30, MGB32, and MGB16 significantly inhibit Acanthamoeba cysts, leading to the development of only 46.3%, 39%, 30.3%, 29.6%, 27.8%, 41.5%, and 45.6% cysts. Additionally, the compounds MGB3, MGB4, MGB6, MGB22, MGB24, MGB28, MGB32, and MGB16 significantly reduce the re-emergence of cysts to trophozoites, with viable trophozoites being only 64.3%, 47.3%, 41.4%, 52.9%, 55.4%, 40.6%, 62.1%, and 51.7%. Moreover, the compounds MGB3, MGB4, and MGB6 exhibited the greatest reduction in amoeba-mediated host-cell death, with cell death reduced to 41.5%, 49.4%, and 49.5%. With the following determined, future in vivo studies can be carried out to understand the effect of the compounds on animal models such as mice.

Antiamoebic Properties of Ceftriaxone and Zinc-Oxide–Cyclodextrin-Conjugated Ceftriaxone

“…Viable amoebae were enumerated using hemocytometer counting and compared with each of the controls. Finally, using concentrations of 50, 75, and 100 µM, the MIC 50 values for the amoebastatic effects were determined [ 24 ].…”

“…To investigate the effects of the employed compounds on A. castellanii encystation, encystation assays were carried out as outlined previously [ 24 , 25 , 26 ]. In short, a count of 1 × 10 6 amoebae was incubated with a concentration of 100 μg/mL of each compound ( Table 1 ) in filtered 16% glucose, with amoebae alone in glucose and amoebae with SDS in glucose serving as negative and positive controls, respectively at 37 °C.…”

Spectroscopic, biochemical and computational studies of bioactive DNA minor groove binders targeting 5′-WGWWCW-3′ motif

“…Ligands were synthesised according to published procedures 2,5,15 being reproduced for convenience to the reader in the Supplementary Information at C1 (description) and by summary in Scheme C1 (see Supporting Information).…”

“…Sequence-specific molecular recognition of the minor groove in double-helical DNA by low molecular weight, aromatic peptides continues as a buoyant field of investigative research. [1][2][3][4][5][6][7][8][9][10][11] The broad class of ligands known as lexitropsins has been widely modified chemically and variously investigated structurally as probes for DNA sequence recognition and particularly as potential therapeutic agents for a variety of diseases [12][13][14][15] . Some of these compounds are now showing promise as future antibiotics capable of overcoming the pervasive and very threatening advance of antibiotic resistance 16 .…”