Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.

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, ß-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.

Structural modification and strategies for the enhanced doxorubicin drug delivery.

Doxorubicin belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. The common side effects of doxorubicin include vomiting, hair loss, rashes to serious side-effects such as irreversible cardiotoxicity, and drug-induced leukemia. This led many researchers around the globe to develop methods aimed to achieve higher efficacy and lower toxicity for doxorubicin. The present review article provides a detailed account of the design strategies i.e., chemical modifications and conjugate formation adopted by various research groups to minimize the side effects without compromising with the significant anticancer profile of the drug doxorubicin. Chemical modification of the drug includes alteration at C4' hydroxyl and C3' amine groups present in the sugar part. The pH-sensitive drug delivery system is covered highlighting use of theranostic tantalum oxide to the traditional approach of conjugating with acyl hydrazine and thiourea. Methods adopted to increase the bioavailability of the drugs inside the cancer cells viz., conjugation with humanized monoclonal antibody and other peptides along with their promising results are also discussed. The review further discusses works from recent years comprising of different nanoforms of doxorubicin for the targeted delivery of drugs inside the tumor cells. Few of the articles targeting nucleus or mitochondria as one of the effective cancer treatments are reported. The brain is inaccessible to the drug and it was modified through galactoxyloglucan-modified gold nanocarrier or conjugated with lactoferrin with enhanced permeability through the blood-brain barrier. Prodrug has particularly been used to target tumor tissues without affecting other tissue organs. The present review article offer clear advantages of one method over another adopted to target the cancer cells and may provide an insight for the researchers working in this area.

COVID19 inhibitors: A prospective therapeutics.

The inhibition of viral targets might provide new therapies for coronavirus disease abbreviated as COVID-19. The rational drug design identified as much of the recent discoveries of potent drugs molecule against any targets. This results in an improvement in bindings for better potency and selectivity. The drugs containing ethanolamine/propylamine fragments along with heterocycles have shown potential antiviral results. Similarly, there is the possibility of controlling the COVID-19 infection by nucleotide analogues. Here we also highlight drugs ACEIs/ARBs inhibitory discussing both their advantages and disadvantages. The class of compounds/antibodies inhibiting interleukin-6 works in antirheumatoid drugs are found useful in alleviating overactive inflammatory responses in the lungs of the patient. These inclusion based approaches counter some of the side-effects associated with the heterocycles and also potentiate the efficacy of the molecules. In this review article, design strategies for some of the drugs effective against SARS-CoV-2 are represented. The review also focuses on the listing of drugs that are currently testing under clinical trials for the COVID-19 virus with their mechanism of action. This conversation undertakes the opportunity to do a bit for the newer researchers working in this arena.