Advancements in the development of multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder which results in cognitive impairment, loss of cholinergic neurons in synapses of the basal forebrain and neuronal death. Exact pathology of the disease is not yet known however, many hypotheses have been proposed for its treatment. The available treatments including monotherapies and combination therapies are not able to combat the disease effectively because of its complex pathological mechanism. A multipotent drug for AD has the potential to bind or inhibit multiple targets responsible for the progression of the disease like aggregated Aß, hyperphosphorylated tau proteins, cholinergic and adrenergic receptors, MAO enzymes, overactivated N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor etc. The traditional approach of one disease-one target-one drug has been rationalized to one drug-multi targets for the chronic diseases like AD and cancer. Thus, over the last decade research focus has been shifted towards the development of multi target directed ligands (MTDLs) which can simultaneously inhibit multiple targets and stop or slow the progression of the disease. The MTDLs can be more effective against AD and eliminate any possibility of drug-drug interactions. Many important active pharmacophore units have been fused, merged or incorporated into different scaffolds to synthesize new potent drugs. In the current article, we have described various hypothesis for AD and effectiveness of the MTDLs treatment strategy is discussed in detail. Different chemical scaffolds and their synthetic strategies have been described and important functionalities are identified in the chemical scaffold that have the potential to bind to the multiple targets. The important leads identified in this study with MTDL characteristics have the potential to be developed as drug candidates for the effective treatment of AD.

Anti-proliferative potential of triphenyl substituted pyrimidines against MDA-MB-231, HCT-116 and HT-29 cancer cell lines.

A series of triphenyl substituted pyrimidines as analogous of colchicine and combretastatin A-4 was synthesized and evaluated for the antiproliferative potential. The compounds were screened against MDA-MB-231, HCT-116 and HT-29 cell lines using MTT assay. Most of the compounds displayed antiproliferative activity in low to sub micro molar concentration. Amongst the synthesized derivatives, compounds HK-2, HK-10 and HK-13 were found to be effective against all the three cancer cell lines. HK-2 exhibited IC50 values of 3.39 µM, 4.78 µM and 4.23 µM, HK-10 showed IC50 values of 0.81 µM, 5.89 µM, 4.96 µM and HK-13 showed IC50 values 3.24 µM, 4.93 µM and 4.73 µM against MDA-MB-231, HCT-116 and HT-29 cancer cell lines, respectively. HK-10 was found to be the most potent compound in the series with IC50 values of 0.81 µM against MDA-MB-231. In the cell cycle analysis, HK-2 and HK-10 showed cell arrest at G2/M phase of the cell cycle while HK-13 inhibited cell growth at the G1/G0 phase. All the three compounds showed cell death induced through apoptosis. In the docking studies, HK-2, HK-10 and HK-13 were found to fit well in the colchicine binding site of the tubulin. Some of the compounds in the current series were found to be promising against all the three cancer cell lines and may act as potent leads for further development.