Synthesis and biological evaluation of selective tubulin inhibitors as anti-trypanosomal agents

Abstract

African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds. One new analog showed great potency with an IC50 of 70 nM to inhibit the growth of trypanosome cells and did not affect the viability of mammalian cells. Western blot analyses reveal that the compound decreased tubulin polymerization in T. brucei cells. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.

SC1 Promotes MiR124-3p Expression to Maintain the Self-Renewal of Mouse Embryonic Stem Cells by Inhibiting the MEK/ERK Pathway

“…7D). The suppression of the MEK/ERK signalling pathway has been shown to promote the self-renewal of mouse ES cells [43, 44]. According to the experimental results, SC1 promotes the expression of miR124-3p and miR124-3p and inhibits MEK/ERK pathway by suppressing the expression of key factors in this pathway: Grb2, Sos2 and Egr1.…”

Trypanosoma vivax infection in sheep: Different patterns of virulence and pathogenicity associated with differentially expressed proteomes

“…The highly conserved eukaryotic tubulins are vital to cell division, motility, intracellular transport, and signal transduction ( Lama et al, 2012 ). Despite tubulin sequence conservation ( Werbovetz et al, 2003 ), there are differences in orthologue susceptibility to antimitotic agents, likely reflecting structural differences among species ( Bobba et al, 2017 , Lama et al, 2012 , Werbovetz et al, 2003 ). The stable biological characteristics of trypanosome tubulin make it an ideal potential drug target and also a prospective vaccine candidate ( Kurup and Tewari, 2012 , Lama et al, 2012 , Li et al, 2007 , Nanavaty et al, 2016 , Werbovetz, 2002 ).…”

Antiproliferative Evaluation and Molecular Docking studies of some Sulfonyl-α-L-amino acid Derivatives coupled with Anisamide Scaffold

“…In recent decades, research into these categories has continued to be active although it has also moved to premium applications [13][14][15][16]. Sulfonamide-bearing compounds have been reported to display antiinflammatory (COX-2 inhibitors) [17], antiproliferative [18][19][20][21], anti-HIV [22,23], anti-Aβ fibrillogenesis [24], and anti-parasitic [25,26], among other properties, and display the diversity of their biological potentials.…”