Discovery of Novel 2-Aryl-4-benzoyl-imidazole (ABI-III) Analogues Targeting Tubulin Polymerization As Antiproliferative Agents

Abstract

Novel ABI–III compounds were designed and synthesized based on our previously reported ABI-I and ABI–II analogs. ABI–III compounds are highly potent against a panel of melanoma and prostate cancer cell lines, with the best compound having an average IC50 value of 3.8 nM. They are not substrate of Pgp and thus may effectively overcome Pgp mediated multidrug resistance. ABI–III analogs maintain their mechanisms of action by inhibition of tubulin polymerization.

Crystal structure of 1-(2H-1,3-benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propan-1-one, C13H12N2O3

“…Their current importance is testified by their ubiquitousness in the fields of medicinal chemistry, material science and agrochemicals [1]. Imidazole-based compounds exhibit diverse biological activities anticancer [2][3][4][5] antibacterial [6,7], antitubercular [8,9], antifungal [10,11], antiviral [12][13][14], anticonvulsant [15][16][17] and antiparkinson's agents [18,19]. The [20][21][22].…”

Discovery of Novel Tubulin Polymerization Inhibitors and Survivin Inhibitors as Potential Anticancer Agents

“…The 3, 4, 5-trimethoxybenzoyl group (C ring) of 12a extends toward the α/β-tubulin interface, similar to the mode of the active parental ABI analogs. [112,115] Unlike 12a which does not possess a large N1-substitution, the much "fatter" RABI 15g cannot fit into the cylinder shaped binding pocket in 3HKD, but dock reasonably well into the shallower pocket in 1SA0. The potential binding mode of 15g was shown in A hydrogen bond between the oxygen of 4-OMe in 15g and SH group of β-CYS241 stabilized the interaction.…”

“…[108,[112][113][114][115][116] Compared with existing tubulin-targeting agents such as paclitaxel, colchicine, or vinblastine, ABI compounds have comparable in vitro and in vivo potency but can effectively circumvent several clinically relevant multidrug resistant mechanisms, including drug resistance mediated by Pgp, multidrug resistance-associated proteins (MRPs), and breast cancer resistant proteins (BCRP). [113][114] ABI compounds have also shown excellent oral bioavailability [113], a potential advantage over existing tubulin inhibitors which can only be administrated by intravenous injection.…”

“…This was accomplished by using previously established synthetic strategies. [108,112,115] Second, we reversed the two major substitutions on the B-ring to produce the 4-aryl-2-benzoyl-imidazoles (reverse ABI, or RABI) compounds. We developed a one-pot synthetic strategy to synthesize RABI analogs in good yields based on the literature for synthesizing similar scaffold.…”

“…Then the cells were continuously incubated with sequential diluted compound solution (10 nM to 100 µM, 100 µl per well) in cell culture medium. After 48 h treatment, the cell viability was determined in MTS assay and IC50 was calculated (n = 4) as described before [112,180].…”