Scaffolds For Drug Discovery Research Articles

Graphitisches Kohlenstoffnitrid als Photokatalysator für die decarboxylative C(sp2)−C(sp3) Kupplung mittels Nickelkatalyse

AbstractDie Entwicklung robuster und zuverlässiger Methoden für den Aufbau von C(sp2)−C(sp3)‐Bindungen ist entscheidend, um eine Vielzahl strukturell diverser Substanzen in der Wirkstoffforschung und ‐entwicklung zugänglich zu machen. Obwohl bedeutende Fortschritte auf diesem Gebiet durch den Einsatz der Metallaphotoredox‐Chemie erzielt wurden, nutzen viele dieser Methoden nach wie vor Photokatalysatoren auf Edelmetallbasis aufgrund ihrer effizienten Redoxprozesse und gut anpassbaren Eigenschaften. Aufgrund der hohen Kosten, Ressourcenknappheit und oftmals erheblichen Toxizität dieser Metalle, ist es von großem Interesse, die Suche nach geeigneten Ersatz voranzutreiben. In dieser Publikation zeigen wir den Einsatz des kommerziell erhältlichen, heterogenen Halbleiters graphitisches Kohlenstoffnitrid (gCN) als Photokatalysator in Kombination mit Nickelkatalyse für die Kreuzkupplung von Arylhalogenid‐ und Carbonsäure‐Derivaten. Wie in vorherigen Berichten gezeigt, kann gCN effektiv an Einelektronenübertragungen (SET) und Energietransfer‐(EnT) Prozessen zur Bildung von C−X‐Bindungen teilnehmen. Dieses Manuskript beinhaltet neue Strategien, um die bislang auf C−O Bindungsknüpfung beschränkten Methoden mittels carbonsäurehaltigen Bausteinen um C−C Bindungsknüpfungen zu erweitern. Es wird gezeigt, dass eine Vielzahl an Arylhalogeniden als auch Carbonsäuren für diese Transformation genutzt werden kann. Im Weiteren wird das Recycling des Photokatalysators demonstriert und der Mechanismus der Reaktion untersucht.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Indoloquinoline Alkaloids as Antimalarials: Advances, Challenges, and Opportunities.

Malaria infections affect almost half of the world's population, with over 200 million cases reported annually. Cryptolepis sanguinolenta, a plant native to West Africa, has long been used across various regions of Africa for malaria treatment. Chemical analysis has revealed that the plant is abundant in indoloquinolines, which have been shown to possess antimalarial properties. Cryptolepine, neocryptolepine, and isocryptolepine are well-studied indoloquinoline alkaloids known for their potent antimalarial activity. However, their structural rigidity and associated cellular toxicity are major drawbacks for preclinical development. This review focuses on the potential of indoloquinoline alkaloids (cryptolepine, neocryptolepine, and isocryptolepine) as scaffolds in drug discovery. The article delves into their antimalarial effects in vitro and in vivo, as well as their proposed mechanisms of action and structure-activity relationship studies. Several studies aim to improve these leads by reducing cytotoxicity while preserving or enhancing antimalarial activity and gaining insights into their mechanisms of action. These investigations highlight the potential of indoloquinolines as a scaffold for developing new antimalarial drugs.

Removing Neighboring Ring Influence in Monocyclic B-OH Diazaborines: Properties and Reactivity as Phenolic Bioisosteres with Dynamic Hydroxy Exchange.

The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B-OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B-OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that N-aryl derivatives are strikingly similar in size and conformation, with attenuated logP values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (Candida albicans), which unveiled analogs with low micromolar inhibitory concentration.

Climbing the Oxidase Phase Ladder by Using Dioxygen as the Sole Oxidant: The Case Study of Costunolide.

Natural sesquiterpenoid lactones are prominent scaffolds in drug discovery. Despite the progress made in their synthesis, their extensive oxidative decoration makes their chemo- and stereoselective syntheses highly challenging. Herein, we report our effort to mimic part of the oxidase phase used in the costunolide pathway to achieve the protecting-group-free total synthesis of santamarine, dehydrocostus lactone, estafiatin, and nine more related natural sesquiterpenoid lactones by using dioxygen as the sole oxidant.

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.

Recent Developments and Future Perspectives of Purine Derivatives as a Promising Scaffold in Drug Discovery.

Numerous purine-containing compounds have undergone extensive investigation for their medical efficacy across various diseases. The swift progress in purine-based medicinal chemistry has brought to light the therapeutic capabilities of purine-derived compounds in addressing challenging medical conditions. Defined by a heterocyclic ring comprising a pyrimidine ring linked with an imidazole ring, purine exhibits a diverse array of therapeutic attributes. This review systematically addresses the multifaceted potential of purine derivatives in combating various diseases, including their roles as anticancer agents, antiviral compounds (anti-herpes, anti-HIV, and anti-influenzae), autoimmune and anti-inflammatory agents, antihyperuricemic and anti-gout solutions, antimicrobial agents, antitubercular compounds, anti-leishmanial agents, and anticonvulsants. Emphasis is placed on the remarkable progress made in developing purine-based compounds, elucidating their significant target sites. The article provides a comprehensive exploration of developments in both natural and synthetic purines, offering insights into their role in managing a diverse range of illnesses. Additionally, the discussion delves into the structure-activity relationships and biological activities of the most promising purine molecules. The intriguing capabilities revealed by these purine-based scaffolds unequivocally position them at the forefront of drug candidate development. As such, this review holds potential significance for researchers actively involved in synthesizing purine-based drug candidates, providing a roadmap for the continued advancement of this promising field.

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.

Tetraasteranes as homologues of cubanes: effective scaffolds for drug discovery.

Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market for a variety of applications, but one notable omission is that of tetraasteranes, which are homologues of cubanes belonging to a class of polycyclic hydrocarbon cage compounds. Tetraasteranes exhibit potential as scaffolds in drug discovery due to their identical cyclobutane structures and rigid conformation resembling cubanes. Based on the studies of the physical and chemical properties of tetraasteranes by density functional theory, three series of compounds were designed as homologues of cubanes by the substitution of cubane scaffolds in pharmaceuticals with tetraasteranes. Their potential for pharmaceutical applications was evaluated in silico by molecular docking and dynamics simulations. Their pharmacokinetic and physicochemical properties were studied by the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The results indicate that tetraasteranes may be scaffolds as novel bioisosteres of cubanes, as well as hydrogen bond donors or acceptors, which enhance the affinity between ligands and receptors with more stable binding behavior and feasible tolerability in ADMET. All these findings provide new opportunities for tetraasteranes to serve as effective pharmaceutical scaffolds for drug discovery and to accelerate the drug discovery process by repurposing both new and old commercial compounds.

Thiazole Heterocycle: An Incredible and Potential Scaffold in Drug Discovery and Development of Antitubercular Agents

AbstractIn 2020, 15 million people were diagnosed with tuberculosis (TB), and 2.4 million died. Additionally, the TB situation is worse with multidrug resistance (MDR) and extended‐drug resistance (XDR)‐TB. Research into innovative anti‐tubercular drugs with improved MDR‐TB activity, lower toxicity, and shorter therapy duration is crucial for solving this issue. Fortunately, numerous novel potential anti‐tubercular candidates are currently under clinical trials. Most of these candidates have five‐membered rings and are most likely effective against sensitive and resistant strains. This review discusses current developments in the five‐membered heterocyclic thiazole ring, emphasizing its anti‐tubercular properties, toxicity, structure‐activity relationship, and mechanism of action. Thiazole ring has a wide range of biological activities and thus gained much synthetic interest. Due to the popularity of thiazole as an anti‐tubercular moiety, it combined with other medicinally active chemical functionality and nuclei to design and synthesize novel hybrid analogues with maximum activity and minimal toxicity. In this review we have done the literature survey of the past 10 years, and compiled the structural and functional studies of thiazole as an anti‐tubercular agent with its potent chemical entities showing prominent pharmacological action.

Structure and activity of new degraded products of limonoid from root bark of Dictamnus dasycarpus, and insights from broadened NMR spectra into self-aggregation of hydroxy acids

Five degraded products of limonoid, including two previously undescribed compounds (1, 3) and one pair of new natural products (4i, 4ii), were isolated from the root bark of Dictamnus dasycarpus Turcz. Their structures were elucidated by extensively spectroscopic methods (NMR, MS, ECD, etc), as well as quantum chemical calculations. The broadening NMR lines, along with the relaxation time and DOSY experiment revealed the self-aggregation of 1 in chloroform through H-bond between –COOH and –OH, which provided additional evidence to distinguish acid and ester/lactone in structure elucidation. Compounds 1–3 attenuated oleic acid-induced lipid accumulation in HepG2 cells significantly, with inhibition rates of 19.8%, 23.6%, and 13.5% at 10 μM, much stronger than fenofibrate, affording a novel scaffold for drug discovery against fatty liver disease.

GraphGPT: A Graph Enhanced Generative Pretrained Transformer for Conditioned Molecular Generation.

Condition-based molecular generation can generate a large number of molecules with particular properties, expanding the virtual drug screening library, and accelerating the process of drug discovery. In this study, we combined a molecular graph structure and sequential representations using a generative pretrained transformer (GPT) architecture for generating molecules conditionally. The incorporation of graph structure information facilitated a better comprehension of molecular topological features, and the augmentation of a sequential contextual understanding of GPT architecture facilitated molecular generation. The experiments indicate that our model efficiently produces molecules with the desired properties, with valid and unique metrics that are close to 100%. Faced with the typical task of generating molecules based on a scaffold in drug discovery, our model is able to preserve scaffold information and generate molecules with low similarity and specified properties.

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.

A Review of the Therapeutic Importance of Indole Scaffold in Drug Discovery.

Indole is known as a versatile heterocyclic building block for its multiple pharmacological activities and has a high probability of success in the race for drug candidates. Many natural products, alkaloids, and bioactive heterocycles contain indole as the active principle pharmacophore. These encourage the researchers to explore it as a lead in the drug development process. The current manuscript will serve as a torchbearer for understanding the structurally diverse class of indole derivatives with extensive pharmacological activity. The current manuscript describes the intermediates and their functional groups responsible for superior biological activity compared to the standard. The review is written to help researchers to choose leads against their target but also to provide crucial insight into the design of a hybrid pharmacophore-based approach in drug design with enhanced potential. The present reviews on the indole derivatives correlate the structures with biological activities as well as essential pharmacophores, which were highlighted. The discussion was explored under challenging targets like dengue, chikungunya (anti-viral), antihypertensive, diuretic, immunomodulator, CNS stimulant, antihyperlipidemic, antiarrhythmic, anti-Alzheimer's, and neuroprotective, along with anticancer, antitubercular, antimicrobial, anti-HIV, antimalarial, anti-inflammatory, antileishmanial, antianthelmintic, and enzyme inhibitors. So, this review includes a discussion of 19 different pharmacological targets for indole derivatives that could be utilized to derive extensive information needed for ligand-based drug design. The article will guide the researchers in the selection, design of lead and pharmacophore, and ligand-based drug design using indole moiety.

A Comparative Analysis of Radical Scavenging, Antifungal and Enzyme Inhibition Activity of 3'-8″-Biflavones and Their Monomeric Subunits.

Biflavonoids are dimeric forms of flavonoids that have recently gained importance as an effective new scaffold for drug discovery. In particular, 3'-8″-biflavones exhibit antiviral and antimicrobial activity and are promising molecules for the treatment of neurodegenerative and metabolic diseases as well as cancer therapies. In the present study, we directly compared 3'-8″-biflavones (amentoflavone, bilobetin, ginkgetin, isoginkgetin, and sciadopitysin) and their monomeric subunits (apigenin, genkwanin, and acacetin) and evaluated their radical scavenging activity (with DPPH), antifungal activity against mycotoxigenic fungi (Alternaria alternata, Aspergillus flavus, Aspergillus ochraceus, Fusarium graminearum, and Fusarium verticillioides), and inhibitory activity on enzymes (acetylcholinesterase, tyrosinase, α-amylase, and α-glucosidase). All the tested compounds showed weak radical scavenging activity, while antifungal activity strongly depended on the tested concentration and fungal species. Biflavonoids, especially ginkgetin and isoginkgetin, proved to be potent acetylcholinesterase inhibitors, whereas monomeric flavonoids showed higher tyrosinase inhibitory activity than the tested 3'-8″-biflavones. Amentoflavone proved to be a potent α-amylase and α-glucosidase inhibitor, and in general, 3'-8″-biflavones showed a stronger inhibitory potential on these enzymes than their monomeric subunits. Thus, we can conclude that 3'-8″-dimerization enhanced acetylcholinesterase, α-amylase, and α-glucosidase activities, but the activity also depends on the number of hydroxyl and methoxy groups in the structure of the compound.

Continuous-Flow Regioselective Reductive Alkylation of Oxindole with Alcohols and Aldehydes in a Fast and Economical Manner

AbstractOxindole is a widely used scaffold in drug discovery, which can be found in several marketed drugs, among them sunitinib and ziprasidone. Thus, the derivatization of oxindole is of considerable current interest. The extreme reaction conditions (high temperature, high pressure) described in the literature for the batchwise regioselective multistep 3-alkylation of oxindole with alcohols in the presence of Raney nickel motivated us to develop a robust, time- and cost-efficient continuous-flow variant for this reaction. In addition, the continuous-flow technology was also extended to the reductive 3-alkylation of oxindole with aldehydes. The elaborated methodology allows the safe use of Raney nickel, an inexpensive and widely applied, albeit pyrophoric catalyst. Under the optimized reaction conditions, 10 oxindole derivatives were synthesized ranging from simple 3-alkyl to 3-aralkyl derivatives including two (trifluoromethyl)benzyl congeners. The technology is considerably robust and the catalyst showed a long-term usability. The model reaction between oxindole and acetaldehyde could be run for 16 hours uninterruptedly, rendering possible the efficient ethylation of about 20 g of oxindole utilizing only approximately 800 mg of Raney nickel.

In Vitro Analyses of the Multifocal Effects of Natural Alkaloids Berberine, Matrine, and Tabersonine against the O'nyong-nyong Arthritogenic Alphavirus Infection and Inflammation.

O'nyong-nyong virus (ONNV) is a member of the reemerging arthritogenic alphaviruses that cause chronic debilitating polyarthralgia and/or polyarthritis via their tropism for the musculoskeletal system. Thus, the discovery of dual antiviral and anti-inflammatory drugs is a great challenge in this field. We investigated the effects of the common plant-derived alkaloids berberine (isoquinoline), matrine (quinolizidine), and tabersonine (indole) at a non-toxic concentration (10 μM) on a human fibroblast cell line (HS633T) infected by ONNV (MOI 1). Using qRT-PCR analyses, we measured the RNA levels of the gene coding for the viral proteins and for the host cell immune factors. These alkaloids demonstrated multifocal effects by the inhibition of viral replication, as well as the regulation of the type-I interferon antiviral signaling pathway and the inflammatory mediators and pathways. Berberine and tabersonine proved to be the more valuable compounds. The results supported the proposal that these common alkaloids may be useful scaffolds for drug discovery against arthritogenic alphavirus infection.

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).

A guide for the synthesis of key nucleoside scaffolds in drug discovery

A guide for the synthesis of key nucleoside scaffolds in drug discovery