Amyotrophic lateral sclerosis (als) is a fatal neurodegenerative disease, characterized by progressive degeneration of motor neurons in brain stem and spinal cord leading to muscular atrophy and paralysis. the earliest symptoms include cramping and stiffness of muscles leading to muscle weakness affecting arms and legs. patients display slurred speech and difficulty in chewing or swallowing. death usually occurs due to complications involving respiratory failure and pneumonia within only 3–5 years after the onset of disease symptoms. als is the third most common neurodegenerative disease after alzheimer’s and parkinson’s disease. the average age of onset of als world-wide is ~ 50 years with a prevalence of ~ 6 individuals per 100,000 each year. in india, the disease onset is estimated to be up to a decade earlier than the worldwide average, at about 40 years, with an annual prevalence rate about 5 per 100,000. it is estimated that nearly 3 lakh people die of als every year in india. mutations in sod1, tdp-43, c9orf72 repeat expansion, fus and several other genes have been implicated in als. smoking has been found to increase the risk of als, either by a direct neurotoxic effect on motor neurons or by increasing oxidative stress. workers in occupations potentially involving exposures to chemicals, pesticides, metals, etc. as well as those with physical trauma like athletes, military personnel, etc. have been found to have an increased als risk. thus far, there is no cure or effective treatment for als. riluzole, which inhibits glutamate excitotoxicity, extends the lifespans of the affected individuals only by 2-3 months. the efficacy of the drug approved by fda in 2017, edaravone (free-radical scavenger) is still being monitored. both these drugs are expensive and difficult to procure. hence, there is immense interest in the development of therapeutic interventions against als. to identify potential drug candidates, here we have investigated the anti-aggregation efficiency of acridine-based small molecules both in vitro and further validated in vivo in a yeast model of tdp-43. different acridine-based small molecules were investigated for inhibitory potential against in vitro tdp-43 aggregation, among which a compound “aim4” displayed the highest aggregation inhibition by up to 80 % at 1:10 protein:inhibitor molar ratio. circular dichroism spectroscopy showed a decrease in β-sheet content by up to 20 % in tdp-43 incubated with aim4. aggregation of tdp-43 is arrested into small, non-amyloidogenic oligomers of 10-20 nm as determined by dynamic light scattering and atomic force microscopy experiments. molecular dynamics simulations studies predict that aim4 interacts with residues within 311 to 323 in the putative amyloidogenic core region of tdp-43. upon further investigating aim4 efficacy in a yeast model for tdp-43, using fluorescence microscopic techniques, aim4-treated yeast cells displayed “diffused fluorescence” or relatively fewer number of tdp-43-yfp “fluorescent dots per cell” compared to untreated yeast cells. strikingly, aim4 also displayed ability to dissolve pre-formed tdp-43-yfp aggregates, a property which is ideal for potential drug candidates. overall, this study finds aim4 as a promising small molecule candidate with anti-tdp-43 aggregation property. for a disease as debilitating & dreaded as als, any result towards finding a therapeutic molecule would be a great step forward.