Multi-component reactions (MCRs) are considered to be an important methodological arsenal in synthetic and medicinal chemistry. These reactions have been strategically employed in various synthetic transformations where classical methods usually involve many steps with tedious procedures. The MCR approach provides high yields, atom-/step economy, reduced reaction time, is eco-friendly, and acts as an amenable tool for the generation of a library of new chemical entities (NCEs), especially in the drug discovery process. Extensive research has led to copious developments in the field of MCRs. The developments have emerged with different synthetic approaches, including C–H activation, coupling, and cycloaddition, and eventually, such an amalgamation has enabled access to a broad spectrum of organic frameworks. The present review summarizes recent advancements in MCRs and their mechanistic insights from the last triennium (2017–2020).

Recent advances in multi-component reactions and their mechanistic insights: a triennium review

Because undesirable pharmacokinetics and toxicity are significant reasons for the failure of drug development in the costly late stage, it has been widely recognized that drug ADMET properties should be considered as early as possible to reduce failure rates in the clinical phase of drug discovery. Concurrently, drug recalls have become increasingly common in recent years, prompting pharmaceutical companies to increase attention toward the safety evaluation of preclinical drugs. In vitro and in vivo drug evaluation techniques are currently more mature in preclinical applications, but these technologies are costly. In recent years, with the rapid development of computer science, in silico technology has been widely used to evaluate the relevant properties of drugs in the preclinical stage and has produced many software programs and in silico models, further promoting the study of ADMET in vitro. In this review, we first introduce the two ADMET prediction categories (molecular modeling and data modeling). Then, we perform a systematic classification and description of the databases and software commonly used for ADMET prediction. We focus on some widely studied ADMT properties as well as PBPK simulation, and we list some applications that are related to the prediction categories and web tools. Finally, we discuss challenges and limitations in the preclinical area and propose some suggestions and prospects for the future.

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Computational Approaches in Preclinical Studies on Drug Discovery and Development.

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO-A/MAO-B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO-B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO-B inhibitors (MAO-BIs) belonging to diverse chemical scaffolds, arising from intensive chemical-mechanistic and computational studies documented during past 3 years (2015-2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO-BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO-BIs with superior activity profiles and critical discussions will inflict more caution in the decision-making process in the MAOIs discovery.

Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update

Chromone derivatives possess a spectrum of biological activities. Chromone has been recognized as a privileged structure for new drug invention and development. Substitution pattern of chromone scaffold determines different type of biological activities. The type, number and position of substituents connected to the chromone core play a vital role in determining pharmacological activities. In the present review, we have discussed new chromone derivatives as anticancer, anti-diabetic, antimicrobial, anti-inflammatory, antioxidant and as anti-Alzheimer agents. This review deals with the chromone derivatives prepared by combining chromone molecule with various natural and synthetic pharmacophores and pharmacological activities presented by them. The main aim is to highlight the diversified pharmacological activities exhibited by chromone hybrid molecules during the last eight to ten years.

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Current Strategies in Development of New Chromone Derivatives with Diversified Pharmacological Activities: A Review

In trying to develop new anticancer agents, a series of sulfonylhydrazones were synthesized. All synthesized compounds were checked for identity and purity using elemental analysis, TLC and HPLC and were characterized by their melting points, FT-IR and NMR spectral data. All synthesized compounds were evaluated for their cytotoxic activity against prostate cancer (PC3), breast cancer (MCF-7) and L929 mouse fibroblast cell lines. Among them, N′-[(2-chloro-3-methoxyphenyl)methylidene]-4-methylbenzenesulfonohydrazide (3k) showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 1.38 μM on PC3 with SI = 432.30 and IC50 = 46.09 μM on MCF-7 with SI = 12.94). Further investigation confirmed that 3k displayed morphological alterations in PC3 and MCF-7 cells and promoted apoptosis through down-regulation of the Bcl-2 and upregulation of Bax expression. Additionally, compound 3k was identified as the most potent COX-2 inhibitor (91% inhibition) beside lower COX-1 inhibition. Molecular docking of the tested compounds represented important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme. Overall, the lead compound 3k deserves further development as a potential anticancer agent. Sulfonylhydrazones was synthesized and N′-[(2-chloro-3-methoxyphenyl)methylidene]-4-
methylbenzenesulfonohydrazide (3k) was identified as the most potent anticancer agent and COX-2
inhibitor. In addition, this compound docked inside the active site of COX-2 succesfully.

Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors

Introduction: Multicomponent reactions (MCR) has been utilized to synthesize a vast range of analogs belonging to diverse classes of heterocyclic compounds offering multidimensional pharmaceutical applications. The unique feature of MCR includes the synthesis of highly functionalized molecules in a single pot to build quick libraries of compounds of biological interest to identify new leads as potential therapeutic agents.Area covered: The current review article covers the patents published in the last decade in order to highlight the importance of multicomponent reactions for synthesizing complex-functionalized molecules of high biological significance.Expert opinion: Easily automated one-pot multicomponent reactions (MCRs) has demonstrated successful impact at different stages of the lead discovery, lead optimization, and pre-clinical process development arenas. Application of MCRs is the recent advancement in the field of drug design and discovery which will expectedly lead to the development of medicinally important heterocyclic compounds with a vast range of biological activities.

Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020).

Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis, molecular modelling and in-silico ADME evaluation.

Hafiza Amna Younus

Papers

Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020).

Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis, molecular modelling and in-silico ADME evaluation.

Sulfonylhydrazones: Design, synthesis and investigation of ectonucleotidase (ALP & e5'NT) inhibition activities.

Piperidinium-Based Deep Eutectic Solvents: Efficient and Sustainable Eco-Friendly Medium for One-Pot N-Heterocycles Synthesis