Privileged Scaffold In Drug Discovery Research Articles

Benzopyrone, a privileged scaffold in drug discovery: An overview of FDA-approved drugs and clinical candidates.

Natural products have always served as an important source of drugs for treating various diseases. Among various privileged natural product scaffolds, the benzopyrone class of compounds has a substantial presence among biologically active compounds. One of the pioneering anticoagulant drugs, warfarin approved in 1954 bears a benzo-α-pyrone (coumarin) nucleus. The widely investigated psoriasis drugs, methoxsalen, and trioxsalen, also contain a benzo-α-pyrone nucleus. Benzo-γ-pyrone (chromone) containing drugs, cromoglic acid, and pranlukast were approved as treatments for asthma in 1982 and 2007, respectively. Numerous other small molecules with a benzopyrone core are under clinical investigation. The present review discusses the discovery, absorption, distribution, metabolism, excretion properties, and synthetic approaches for the Food and Drug Administration-approved and clinical-stage benzopyrone class of compounds. The role of the pyrone core in biological activity has also been discussed. The present review unravels the potential of benzopyrone core in medicinal chemistry and drug development.

Synthesis and Antioxidant Activities of Novel Pyrimidine Acrylamides as Inhibitors of Lipoxygenase: Molecular Modeling and In Silico Physicochemical Studies.

The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer activities and can be considered as privileged scaffolds in drug discovery for the treatment of various diseases. Piperidine pyrimidine amides have gained significant attention due to their enzymatic inhibitory activity. Based on our experience and ongoing investigation on cinnamic acid derivatives, their hybrids and substituted pteridines acting as lipoxygenase inhibitors, antioxidants, anti-cancer, and anti-inflammatory agents a series of novel piperidine pyrimidine cinnamic acids amides have been designed and synthesized. The novel hybrids were studied for their antioxidant and anti-inflammatory potential. They exhibit moderate antioxidant activity in the DPPH assay which may be related to their bulkiness. Moreover, moderate to good lipid peroxidation inhibition potential was measured. With regards to their lipoxygenase inhibitory activity, however, two highly potent inhibitors out of the nine tested derivatives were identified, demonstrating IC50 values of 10.7 μM and 1.1 μM, respectively. Molecular docking studies to the target enzyme lipoxygenase support the experimental results.

Improved Synthetic Methodology, Substrate Scope and X‐ray Crystal Structure for N, N’‐disubstituted Guanidines

AbstractGuanidine is a privileged scaffold in drug discovery. Herein we report our investigations into the acid promoted amination of pyrimidine‐bearing cyanamide to produce N, N’‐disubstituted guanidines. Hydrochloric acid was found to be a suitable catalyst, and the substrate scope using conventional heating was investigated with 23 aniline derivatives. The highest yield was obtained with anilines having pKa in the range of 2–4. Further, a microwave synthesis was developed using 3‐chloroaniline as a model substrate increasing the yield from 68 to 93 %. The microwave method was especially suited for increasing yields with anilines having pKa > 3. The structure of the pyrimidine‐bearing guanidines was confirmed by NMR spectroscopy, and one representative compound has been evaluated by X‐ray crystallography, showing the trans‐isomer as the only tautomer in solid form.

Pyrazole: an emerging privileged scaffold in drug discovery.

Pyrazole or 1H-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing a pyrazole nucleushas increased significantly in the last 10years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, nirapariband baricitinib, and are usedto treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Here, we discuss the pyrazole-deriveddrugsreported up to September 2023.

Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[d]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists.

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).

Cytotoxic pyridine alkaloids from a marine-derived fungus Arthrinium arundinis exhibiting apoptosis-inducing activities against small cell lung cancer

Small cell lung cancer (SCLC) is a kind of high-grade neuroendocrine carcinoma, which is characterized by a higher proliferative rate, earlier metastasis and more poor outcomes compared to non-small cell lung cancer (NSCLC). Under the guidance of MS/MS based molecular networking, three undescribed pyridone alkaloids, namely, arthpyrones M–O (1–3), together with two known pyridone derivatives, arthpyrones C (4) and G (5), were isolated from a sponge-derived Arthrinium arundinis. Their structures were determined through extensive spectroscopic analysis, ECD calculations, and X-ray single-crystal diffraction. Arthpyrone M (1) possessed a novel cage structure bearing an ether bridge functionality rarely reported in this class of metabolites. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1–5 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.26 to 6.43 μM. Among them, arthpyrone O (3) not only exhibited potent efficacy against the proliferative activity of SCLC cells and induced apoptosis in vitro, but also significantly inhibited the growth of xenograft tumor based on SCLC cells in vivo, which indicated 4-hydroxy-2-pyridone alkaloids might been revised as privileged scaffolds in drug discovery.

Microwave‐Assisted Synthesis of Phthalazinone Derivatives with Biological Activity and In Silico Antiproliferative Studies

AbstractSeveral nitrogen heterocycles are considered as privileged scaffolds in drug discovery and are present in several drugs with diverse biological activities. Herein, we report the synthesis and characterization of phthalazinone derivatives by using a green synthesis protocol under microwave irradiation. The reduced reaction time and high yield are some of the advantages that render this procedure a greener alternative to conventional chemical synthesis. The structures of all new derivatives were confirmed by spectral analysis. Synthesized derivatives show an effective antimicrobial effect. These compounds were also screened for their in vitro anticancer activity against colon cancer cell line (HCT116). Among the synthesized derivatives are exhibited the highest anticancer activity with IC50 of 28.97±0.11, 66.25±0.14 and 76.04±0.09 μM respectively. The antiproliferative activity was supported by molecular docking studies that showed that phthalazinone derivatives would potentially act through inhibition of PARP. The simulation studies substantiated the biological results as an active compounds in term of binding interactions and scores.

Regioselective Synthesis of 2-Aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides Self-Assisted by a 2-Hydroxyaryl Group.

The reactivity of the diaminomaleonitrile-based imines containing hydroxyphenyl substituents with diverse aromatic aldehydes has been explored for the synthesis of novel highly substituted nitrogen heterocycles, which are considered privileged scaffolds in drug discovery. We report here a simple and efficient method for the regiocontrolled synthesis of a variety of 2-aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides from 2-hydroxybenzylidene imines and aromatic aldehydes. Computational studies on the reaction path revealed that the regioselectivity of the reaction toward the formation of imidazole derivatives instead of 1,2-dihydropyrazines, most likely via a diaza-Cope rearrangement, is driven by the 2-hydroxyaryl group in the scaffold. The latter group promotes the intramolecular abstraction and protonation process in the cycloadduct intermediate, triggering the evolution of the reaction toward the formation of imidazole derivatives.

Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy

Natural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3′-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor activity. Among them, compound 8b revealed 55.15% and 55.50% inhibition for Top1 and Top2 at 25 μM, as well as 0.16 and 0.13 μM IC50 value for MGC-803 and SGC-7901 cells, respectively; compound 9a revealed 70.50% and 71.81% inhibition for Top1 and Top2 at 25 μM, as well as 0.22 and 0.27 μM IC50 value for MGC-803 and SGC-7901 cells, respectively. The further biological evaluation showed that they could functionally induce apoptosis, significantly arrest the cell cycle at the G2/M phase, and markedly inhibit cell proliferation, migration and invasion. In addition, compound 9a performed a tumor inhibitory rate of 36.35% and showed no apparent toxicity in vivo. Overall, these optimized protocols will advance the progression of cancer chemotherapy and can be used to expand the options for screening therapeutic cancer drugs.

Bioactive 2-pyridone-containing heterocycle syntheses using multicomponent reactions.

2-Pyridone-containing heterocycles are considered privileged scaffolds in drug discovery due to their behavior as hydrogen bond donors and/or acceptors and nonpeptidic mimics, and remarkable physicochemical properties such as metabolic stability, solubility in water, and lipophilicity. This review provides a comprehensive overview of multicomponent reactions (MCRs) for the synthesis of 2-pyridone-containing heterocycles. In particular, it covers the articles published from 1999 to date related to anticancer, antibacterial, antifungal, anti-inflammatory, α-glucosidase inhibitor, and cardiotonic activities of 2-pyridone-containing heterocycles obtained exclusively by an MCR. The discussion focuses on bioactivity data, synthetic approaches, plausible reaction mechanisms, and molecular docking simulations to facilitate comparison and underscore the applications of the 2-pyridone motif in drug discovery and medicinal chemistry. We also present our conclusions and outlook for the future.

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S RN 1-Debromination Approach

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

The Importance of Rhodanine Scaffold in Medicinal Chemistry: A Comprehensive Overview.

After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry. Various modifications to the rhodanine ring have led to a broad spectrum of biological activity of these compounds. Synthesis of rhodanine derivatives, depended on advenced throughput scanning hits, frequently causes potent and selective modulators of targeted enzymes or receptors, which apply their pharmacological activities through different mechanisms of action. Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have, therefore reviewed their biological activities and structure activity relationship.

Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery.

Drug discovery has traditionally focused on using libraries of small molecules to identify therapeutic drugs, but new modalities, especially libraries of genetically encoded cyclic peptides, are increasingly used for this purpose. Several technologies now exist for the production of libraries of cyclic peptides, including phage display, mRNA display and split-intein circular ligation of peptides and proteins. These different approaches are each compatible with particular methods of screening libraries, such as functional or affinity-based screening, and screening in vitro or in cells. These techniques allow the rapid preparation of libraries of hundreds of millions of molecules without the need for chemical synthesis, and have therefore lowered the entry barrier to generating and screening for inhibitors of a given target. This ease of use combined with the inherent advantages of the cyclic-peptide scaffold has yielded inhibitors of targets that have proved difficult to drug with small molecules. Multiple reports demonstrate that cyclic peptides act as privileged scaffolds in drug discovery, particularly against 'undruggable' targets such as protein-protein interactions. Although substantial challenges remain in the clinical translation ofhits from screens of cyclic-peptide libraries, progress continues to be made in this area, with an increasing number of cyclic peptides entering clinical trials. Here, we detail the various platforms for producing and screening libraries of genetically encoded cyclic peptides and discuss and evaluate the advantages and disadvantages of each approach when deployed for drug discovery.

3',4'-Dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening.

Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities including anti-cancer activity, and are therefore recognized as two privileged scaffolds in drug discovery. In the present study, 24 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, designed as molecular hybrids of THIQ and OX, were synthesized and screened in vitro against 59 cell lines in the NCI-60 screen. Twenty compounds displayed weak to moderate inhibition of cell proliferation; among them, three compounds displayed at least 50% inhibition of cell proliferation. The compounds appeared to target primarily renal cell cancer lines; however, leukaemia, melanoma, non-small cell lung cancer, prostate, ovarian and even breast cancer cell lines were also affected. Therefore, this class of spirooxindoles may provide useful leads in the search for new anti-cancer agents.

Carbazole Derivatives as Antiviral Agents: An Overview.

Viruses represent the most common cause of infectious diseases worldwide and those with rapid propagation and high infection rates cause human and animal pandemics. These fast-spreading diseases are generally treated with antiviral drugs but, often, drug resistance occurs because of the ability of the pathogens to mutate rapidly and become less susceptible to the treatments. Even though new antivirals have been approved, e.g., in HIV (human immunodeficiency virus) and HCV (hepatitis C virus) therapeutic areas, the need to dispose of new pharmaceutical tools for the management of infections that still have no treatment is of growing interest. In these areas, carbazole represents an important privileged scaffold in drug discovery. Many compounds with a carbazolic core have been developed and some of them have shown antiviral activity. This review provides an overview on some already known carbazole derivatives, pointing the attention on the running progresses in identifying new molecules with carbazolic structure, that have shown interesting and encouraging in vitro and in vivo properties. These drugs may be exploited as valid alternatives in antiviral therapy.

Catalyst-free glycerol-mediated green synthesis of 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-diones

ABSTRACTThe development of new catalyst-free green and efficient protocol to access 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-diones, potential privileged scaffolds for drug discovery, is disclosed. Key feature of this methodology is the dual use of glycerol—a recyclable, bioorganic compound, as a solvent cum promoter. Other highlights include use of inexpensive reagents, mild reaction conditions, operational simplicity, short reaction time, no need for chromatographic purification, and high yields.

ChemInform Abstract: A Review on Recent Developments of Indole‐Containing Antiviral Agents

AbstractReview: 125 refs.

A Metal‐Catalyzed Tandem 1,4‐Benzodiazepine Synthesis Based on Two Hydrogen‐Transfer Reactions

AbstractStarting from 2‐aminobenzyl alcohols and 1,2‐amino alcohols, 2,3,4,5‐tetrahydro‐1H‐1,4‐benzodiazepines (TH‐BDZ) can be prepared through a one‐pot ruthenium‐catalyzed reaction encompassing two consecutive borrowing hydrogen cycles. First, benzyl alcohol oxidation, condensation with the amino alcohol, and imine reduction occurs. This is followed by oxidation of the other alcohol functionality and reductive cyclocondensation to give the TH‐BDZ derivatives. A single catalyst does the entire job, with two molecules of water being the only waste product. Many new substituted 2,3,4,5‐tetrahydro‐1H‐1,4‐benzodiazepines have been prepared to demonstrate the versatility of this method, which can be used for the preparation of privileged scaffolds for drug discovery.

A review on recent developments of indole-containing antiviral agents.

Indole represents one of the most important privileged scaffolds in drug discovery. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes, which provide tremendous opportunities to discover novel drugs with different modes of action. There are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. There are also an amazing number of approved indole-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. This review focused on the recent development of indole derivatives as antiviral agents with the following objectives: 1) To present one of the most comprehensive listings of indole antiviral agents, drugs on market or compounds in clinical trials; 2) To focus on recent developments of indole compounds (including natural products) and their antiviral activities, summarize the structure property, hoping to inspire new and even more creative approaches; 3) To offer perspectives on how indole scaffolds as a privileged structure might be exploited in the future.

Chromones as a privileged scaffold in drug discovery: A review

The chromone and its derivatives are the most important heterocyclic compounds, which is a common and integral feature of a variety of natural products and medicinal agents. These heterocycles show a variety of pharmacological properties, and change of their structure offers a high degree of diversity that has proven useful for the search of new therapeutic agents. A large volume of research has been carried out on chromone and their derivatives, which has proved the pharmacological importance of this heterocyclic nucleus. The present review focuses on the pharmacological profile of chromone derivatives in the current literature with an update of recent research findings on this nucleus and the perspectives that they hold for future research.