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Alzheimer's disease (AD) is a neurological disorder that leads to dementia i.e., progressive memory loss accompanied with worsening of thinking ability of an individual. The cause of AD is not fully understood but it progresses with age where brain cells gradually die over time. According to the World Health Organization (WHO), currently 50 million people worldwide are affected by dementia and 60-70% of the cases belong to AD. Cumulative research over the past few decades have shown that molecules that act at a single target possess limited efficacy since these investigational drugs are not able to act against complex pathologies and thus do not provide permanent cure. Designing of multi-target directed ligands (MTDLs) appears to be more beneficial and a rational approach to treat chronic complex diseases including neurodegenerative diseases. Recently, MTDLs are being extensively researched by the medicinal chemists for the development of drugs for the treatment of various multifactorial diseases. Indole is one of the privileged scaffolds which is considered as an essential mediator between the gut-brain axis because of its neuroprotective, anti-inflammatory, β-amyloid anti-aggregation and antioxidant activities. Herein, we have reviewed the potential of some indole-hybrids acting at multiple targets in the pathogenesis of AD. We have reviewed research articles from the year 2014-2021 from various scientific databases and highlighted the synthetic strategies, mechanisms of neuroprotection, toxicity, structure activity relationships and molecular docking studies of various indole-hybrid derivatives. This literature review of published data on indole derivatives indicated that developing indole hybrids have improved the pharmacokinetic profile with lower toxicity, provided synergistic effect, helped to develop more potent compounds and prevented drug-drug interactions. It is evident that this class of compounds have potential to inhibit multiple enzymes targets involved in the pathogenesis of AD and therefore indole hybrids as MTDLs may play an important role in the development of anti-AD molecules.

Dihydropyrimidinones are extremely advantageous small sized molecules owning adaptable pharmaceutical properties. With a molecular formula C4H6N2O, they hold a wide range of biological activities. It is a heterocyclic moiety having two N-atoms at positions 1 and 3. They are derivatives of pyrimidine containing an additional ketone group. They have inspired development of a wide range of synthetic methods for preparation and chemical transformations. Taking into consideration their structural similarity and involvement with DNA and RNA, they have become very imperative in the world of synthetic organic chemistry. Aryl substituted moieties and their derivatives are significant class of substances in medicinal and organic chemistry. Many alkaloids from natural marine sources comprising dihydropyrimidinones core have been isolated which possess fascinating biological properties. Intensive explorations have been carried out on these compounds because they possess close similitude to clinically used nifedipine, nicardipine etc. which are also Biginelli product analogues. Due to the interesting pharmacological properties associated with the privileged DHPM structures, the Biginelli reaction and related procedures have received increasing attention in recent years.

Objective: The objective of the study was to explore in silico design, preparation, characterization, and evaluation in vitro of some novel 4H-chromene derivatives as anti-inflammatory and antioxidant agents. Methods: 4-phenyl-4H chromene derivatives were imperiled to in silico modeling studies at the molecular level. The ligands were docked against cyclooxygenase-2 (COX-2) receptor targets using Argus Lab. Based on the result, the derivatives were selected for wet lab synthesis. A highly efficient multicomponent reaction of 4H chromene was carried out by one-step condensation of aldehyde with malononitrile and resorcinol without catalyst in water under ultrasound irradiation. The prepared compounds were characterized by noting their melting point, ultraviolet (UV) spectroscopy, infrared (IR) spectroscopy, and thin layer chromatography (TLC) and were scrutinized for its in vitro anti-inflammatory and antioxidant activitives by in vitro cell culture studies. IR spectra of the two compounds were analyzed and studied. Thus, using melting point, TLC and UV spectroscopy the synthesized compounds were found to be pure and identified chemically. The synthesized compounds were then screened for in vitro antioxidant (by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide free radical scavenging) activity and anti-inflammatory activity by Raw 264.7 cell lines. Result: From the study, it was noticed that chemical structure-2 showed better antioxidant and anti-inflammatory activitives than chemical structure. In the 4-phenyl-4H chromene derivatives, hydroxyl substitution at 7th position and electronegative halogen at 4th position showed better antioxidant and anti-inflammatory activities. Conclusion: The results disclosed that these synthesized derivatives be likely to have moderate action against COX-2 mediated diseases, thereby it may lessen inflammation and agony because of its antioxidant and anti-inflammatory activitives.