Imidazolium tagged acridines: Synthesis, characterization and applications in DNA binding and anti-microbial activities

An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models

“…1). These compounds have two methylimidazolium groups at the C-4 and C-5 positions of the planar acridine skeleton and differ in the side chains attached to the imidazolium and also in the counter anions associated with the positive charge on the imidazolium groups37. By examining TDP-43 2C aggregation using ThT fluorescence assay, we found that among these compounds examined at 1:10 (Protein: Compound) molar ratio, the compound AIM4, which contains two carboxyl groups in the side chains, caused the maximum decrease in ThT fluorescence intensity (up to 76%) (Fig.…”

“…Although, the backbone structure is same in the AIM2, AIM3 & AIM5 compounds, they differ in the counter ions. The PF 6 − counter ion in AIM2, BF 4 − counter ion in AIM3 & the Br − counter ion in AIM5, can play an important role in tuning the acidity of the imidazole C-H proton, which is responsible for the N(N)C-H····X, hydrogen bonding strength373839. The observed difference in the TDP-43 2C inhibition ability of AIM2 compared to AIM3 & AIM5, may possibly be due to their differential interaction capabilities with the protein molecule due to altered hydrogen bonding abilities.…”

“…Furthermore, it concurrently also rules out the possibility that the differences in the counter-ions in AIM4 versus AIM2 & AIM3 are solely responsible for the difference in their inhibitory abilities. As these acridine compounds are also intrinsically fluorescent37, control experiments were performed to eliminate their any possible quenching effect on the ThT fluorescence (Supplementary Fig. S1).…”

“…In fact, sequestration of TDP-43 in stress granules in a cell which comprises of other proteins such as TIA-1 & RNA molecules has been proposed as a priming mechanism for aggregation of TDP-437. In the view that AIM4 also has binding ability to nucleic acids37, the observed reduction in TDP-43-YFP aggregation could also be due to a combinatorial effect of interaction of AIM4 with TDP-43 as well as any other cellular components that may be involved in aiding the aggregation of TDP-43.…”

“…For comparison, another derivative of acridine, 4,5-bis(hydroxymethyl)acridine, which lacks imidazole in the side arms but contains polar hydroxymethyl groups at carbon 4 & 5 of acridine, was also examined for anti-aggregation ability against TDP-43. The effect of these compounds on in vitro aggregation of TDP-43’s C-terminal amyloidogenic fragment (TDP-43 2C ), using tools like ThT fluorescence, circular dichroism, and AFM37. Furthermore, we have also examined if there is anti-aggregation effect on full-length TDP-43 tagged with YFP using the eukaryotic single cell yeast model by fluorescence microscopy.…”