Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by decreased synaptic transmission and cerebral atrophy with appearance of amyloid plaques and neurofibrillary tangles. Cognitive, functional, and behavioral alterations are commonly associated with the disease. Different pathophysiological pathways of AD have been proposed, some of which interact and influence one another. Current treatment for AD mainly involves the use of therapeutic agents to alleviate the symptoms in AD patients. The conventional single-target treatment approaches do not often cause the desired effect in the disease due to its multifactorial origin. Thus, multi-target strategies have since been undertaken, which aim to simultaneously target multiple targets involved in the development of AD. In this review, we provide an overview of the pathogenesis of AD and the current drug therapies for the disease. Additionally, rationales of the multi-target approaches and examples of multi-target drugs with pharmacological actions against AD are also discussed.

Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate citrullinated proteins. Apart from carrying out citrullination in the periodontium, the bacterium is found capable of citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. Studies have suggested that both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease. Thus, inhibition of these virulence factors not only can mitigate periodontitis, but also can provide new therapeutic solutions for systematic diseases involving bacterial citrullination. Herein, we described both these proteins in terms of their unique structural conformations and biological relevance to different human diseases. Moreover, investigations of inhibitory actions on the enzymes are also enumerated. New approaches for identifying inhibitors for peptidyl arginine deiminase through drug repurposing and virtual screening are also discussed.

Human A₃ adenosine receptor hA₃AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A_2A adenosine receptor (hA_2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A_2A activity and instead conferred hA₃AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA₃AR partial agonist, with an E_max of 30% and EC₅₀ of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA₃AR partial agonists for the treatment of gastrointestinal cancers.