Medicinal Chemistry Research Articles

Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability.

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pKa is significantly lower than the basic pKa. Through concordance of measured and calculated pKa and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpKa. These nonclassical zwitterions are characterized by a weak acidic and basic pKa and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

Recent Advances in the Synthesis of Diarylheptanoids.

In the quest for synthesizing biologically important natural products, medicinal chemists embark on an endless journey. This review focuses on the reports published towards the syntheses of diarylheptanoids, classifying them into linear, tetrahydropyran, diarylether, and biphenyl categories. The synthesis methods for each class from 2013 to 2023 are discussed, providing a comprehensive overview of the advancements in the field. Representative natural product examples are highlighted for each category. The review emphasizes the importance of diarylheptanoids in the realms of chemistry and medicine, showcasing their potential as valuable compounds for medicinal and synthetic chemists.

Synthesis of Azo-Substituted Bicyclo[1.1.1]pentanes (BCPs) via Base-Promoted Halogen Atom Transfer.

Because of the three-dimensional bioisosteric feature, bicyclo[1.1.1]pentylamines (BCPAs) are valuable scaffolds in synthetic chemistry and medicinal chemistry. Here, we report a Halogen Atom Transfer (XAT) mediated radical C-N coupling between C3-iodo-BCPs and diazonium salts in the presence of base. Similarly, a multicomponent reaction (MCR) enables the simultaneous construction of the C-C bond and C-N bond simultaneously. Versatile roles of diazonium salts were also explored.

Chemical Derivatization Leads to the Discovery Of Novel Analogs of Azotochelin, a Natural Siderophore, as Promising Anticancer Agents.

Siderophores are structurally unique medicinal natural products and exhibit considerable therapeutic potential. Herein, we report the design and synthesis of azotochelin, a natural siderophore, and an extensive library of azotochelin analogs and their anticancer properties. We modified the carboxylic acid and the aromatic ring of azotochelin using various chemical motifs. We evaluated the cytotoxicity of the compounds against six different cancer cell lines (KB-3-1, SNB-19, MCF-7, K-562, SW-620, and NCI-H460) and a non-cancerous cell line (HEK-293). Among the twenty compounds tested, the IC50 values of nine compounds (14, 32, 35-40, and 54) were between 0.7 and 2.0 μM against a lung cancer cell line (NCI-H460). Moreover, several compounds showed good cytotoxicity profile (IC50 <10 μM) against the tested cancer cell lines. The flow cytometry analysis showed that compounds 36 and 38 induced apoptosis in NCI-H460 in a dose-dependent manner. The cell cycle analysis indicated that compounds 36 and 38 significantly arrested the cell cycle at the S phase to block cancer cell proliferation in the NCI-H460 cell line. The study has produced various novel azotochelin analogs that are potentially effective anticancer agents and lead compounds for further synthetic and medicinal chemistry exploration.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. The review highlights anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazolescapacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness.Based oninformation provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and medical community as a whole.Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

A Recent Trends on Green Synthesis and Bioactivity of Imidazole

Imidazole is a five-membered, planar heterocyclic ring made up of 3C, 2N, and N in the 1st and 3rd places. Purine, histamine, histidine, and nucleic acid are only a few significant natural compounds that contain the imidazole ring. It is utilised as a cure to optimize the solubility and bioavailability properties of proposed weakly soluble lead compounds since it is an aromatic chemical that is polar and ionizable and so improves the pharmacokinetic features of lead molecules. Derivatives of imidazole have a special place in medicinal chemistry. An essential synthesis technique in the process of discovering new drugs is the integration of the imidazole nucleus. Due to the remarkable therapeutic efficacy of medications related to imidazole, medicinal chemists have been inspired to create numerous innovative chemotherapy agents. This review summarized the work that has been done in recent years about different synthetic approaches of imidazole derivatives and their potential activity as anti-HIV, anticancer, anticovid, antifungal, antidiabetic, antidepressant, antioxidant, and antituberculosis.

Benzamide Trimethoprim Derivatives as Human Dihydrofolate Reductase Inhibitors—Molecular Modeling and In Vitro Activity Study

Human dihydrofolate reductase (hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (TMP) as a model compound in our search for a new class of hDHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of TMP analogs. In this work, we present previously obtained and evaluated eleven benzamides (JW1–JW8; MB1, MB3-MB4). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). JW8 was most active against AChE, with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC50 value was 9.01 µM compared to that for quercetin, with IC50 = 4.89 µM. All the benzamides were active against hDHFR, with IC50 values ranging from 4.72 to 20.17 µM, and showed activity greater than TMP (55.26 µM). Quantitative results identified the derivatives JW2 and JW8 as the most promising. A molecular modeling study demonstrates that JW2 interacts strongly with the key residue Gly-117, while JW8 interacts strongly with Asn-64 and Arg-70. Furthermore, JW2 and JW8 demonstrate the ability to stabilize the hDHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry.

Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery.

Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C-H bonds with more stable C-D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C-H bonds to C-D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years. Although various deuterated drug candidates undergo clinical trials, approved deuterated drugs possess CD3 groups in the same molecule. However, less diversification, except for the CD3 group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (dn-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using D2O as an inexpensive deuterium source to introduce CD3, CH3CD2, and ArCH2CD2 groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD3 group, and our newly developed electrophilic dn-alkyl reagents are discussed.

Two-Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I poison.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

Cell Therapies and Gene Therapy for Diabetes: Current Progress.

The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery.

The exploration of chemical space for disease targets is of paramount importance. However, the current repertoire of chemically synthesized compounds, numbering around 108, merely scratches the surface in comparison to the theoretical diversity of 1060. Organic chemists are actively engaged in pioneering methodologies to expand this constrained space. Among these innovative approaches, Asymmetric Carbene Transfer (ACT) emerges as a potent strategy for enhancing molecular diversity. This article critically examines the efficacy of ACT in synthesizing pharmaceutically relevant molecules, encompassing natural products and bioactive compounds. We highlight its pivotal role in the synthesis of 25 compounds. By unraveling the diverse applications of ACT, this review illuminates its potential impact on drug discovery. Furthermore, we propose future methodology directions, contributing to the ongoing discourse within the medicinal chemistry community. In summary, this review article navigates the landscape of ACT, showcasing its prowess in expanding chemical space for drug discovery. Through a nuanced exploration of its applications and a forward-looking approach, we contribute to the collective understanding of ACT's potential and chart a course for future advancements in ACT for drug discovery.

Recent Advances in Manganese(III)-Assisted Radical Cyclization for the Synthesis of Natural Products: A Comprehensive Review

Natural products play an important part in synthetic chemistry since they have many pharmacological properties and are used as active drug compounds in pharmaceutical chemistry. However, synthesis of these complex molecules is difficult due to the requirement of various synthetic steps, which include highly regio- and stereoselectivity. Therefore, oxidative radical cyclization assisted by manganese(III) acetate serves as an important step in obtaining spiro-, tricyclic, tetracyclic, and polycyclic derivatives of these compounds. Manganese(III)-based reactions offer a single-step regio- and stereoselective cyclizations and α-acetoxidations, reducing the number of synthetic steps. Also, the manganese(III)-mediated oxidative free radical cyclization method has been successfully applied for the synthesis of cyclic structures found in many natural products. This article presents a broad overview of manganese(III)-based radical reactions of natural products as a key step in overall synthesis. The authors have classified natural product synthesis processes assisted by manganese(III) acetate as intermolecular, intramolecular, oxidation, acetoxidation, aromatization, and polymerization reactions, respectively.

Cooperative Photoredox and Cobalt-Catalyzed Acceptorless Dehydrogenative Functionalization of Cyclopropylamides towards Allylic N,O-Acyl-acetal Derivatives.

We disclose herein a novel photoredox and cobalt co-catalyzed ring-opening/acceptorless dehydrogenative functionalization of mono-donor cyclopropanes. This sustainable and atom-economic approach allows the rapid assembly of a wide range of allylic N,O-acyl-acetal derivatives. The starting materials are readily available and the reaction features mild conditions, broad substrate scope, and excellent functional group compatibility. The optimized conditions accommodate assorted cycloalkylamides and primary, secondary, and tertiary alcohols, with applications in late-stage functionalization of pharmaceutically relevant compounds, stimulating further utility in medicinal chemistry. Moreover, selective nucleophilic substitutions with various carbon nucleophiles were achieved in a one-pot fashion, offering a reliable avenue to access some cyclic and acyclic derivatives.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Cooperative Photoredox and Cobalt‐Catalyzed Acceptorless Dehydrogenative Functionalization of Cyclopropylamides towards Allylic N,O‐Acyl‐acetal Derivatives

AbstractWe disclose herein a novel photoredox and cobalt co‐catalyzed ring‐opening/acceptorless dehydrogenative functionalization of mono‐donor cyclopropanes. This sustainable and atom‐economic approach allows the rapid assembly of a wide range of allylic N,O‐acyl‐acetal derivatives. The starting materials are readily available and the reaction features mild conditions, broad substrate scope, and excellent functional group compatibility. The optimized conditions accommodate assorted cycloalkylamides and primary, secondary, and tertiary alcohols, with applications in late‐stage functionalization of pharmaceutically relevant compounds, stimulating further utility in medicinal chemistry. Moreover, selective nucleophilic substitutions with various carbon nucleophiles were achieved in a one‐pot fashion, offering a reliable avenue to access some cyclic and acyclic derivatives.

Recent Developments in the Ruthenium‐Catalyzed Azide Alkyne Cycloaddition (RuAAC) Reaction

The ruthenium‐catalyzed azide alkyne cycloaddition (RuAAC) gives access to 1,5‐disubstitued triazoles in a single atom‐economical step and offers advantages compared to its copper‐catalyzed counterpart in that both terminal and internal alkynes can be employed. This review summarized recent findings in this field during the last eight years, covering mechanistic investigations, synthetic developments, as well as applications in medicinal chemistry, polymer synthesis and physical organic chemistry

Tamarix aphylla derived metabolites ameliorate indomethacin-induced gastric ulcers in rats by modulating the MAPK signaling pathway, alleviating oxidative stress and inflammation: In vivo study supported by pharmacological network analysis.

Nature has proven to be a treasure resource of bioactive metabolites. In this regard, Tamarix aphylla (F. Tamaricaceae) leaves crude extract was investigated for its gastroprotective effect against indomethacin-induced damage to the gastric mucosa. Additionally, phytochemical investigation of the methanolic extract afforded eight flavonoids' derivatives (1-8). On pharmacology networking study, the isolated compounds identified 123 unique targets where only 45 targets were related to peptic ulcer conditions, these 45 targets include 11 targets specifically correlate to gastric ulcer. The protein-protein interaction defined the PTGS2 gene as one of the highly interacted genes and the complete pharmacology network defined the PTGS2 gene as the most represented gene. The top KEGG signaling pathways according to fold enrichment analysis was the EGFR tyrosine kinase inhibitor resistance pathway. As a result, these findings highlighted the significance of using T. aphylla leaves crude extract as an anti-gastric ulcer candidate, which provides a safer option to chemical antisecretory medicines, which are infamous for their negative side effects. Our findings have illuminated the potent anti-inflammatory and antioxidant effects of T. aphylla, which are likely mediated by suppressing IL-1β, IL-6, TNF-α, and MAPK signaling pathways, without compromising gastric acidity.

From deep learning to the discovery of promising VEGFR-2 inhibitors.

Vascular endothelial growth factor receptor 2 (VEGFR-2) stands as a prominent therapeutic target in oncology, playing a critical role in angiogenesis, tumor growth, and metastasis. FDA-approved VEGFR-2 inhibitors are associated with diverse side effects. Thus, finding novel and more effective inhibitors is of utmost importance. In this study, a deep learning (DL) classification model was first developed and then employed to select putative active VEGFR-2 inhibitors from an in-house chemical library including 187 druglike compounds. A pool of 18 promising candidates was shortlisted and screened against VEGFR-2 by using molecular docking. Finally, two compounds, RHE-334 and EA-11, were prioritized as promising VEGFR-2 inhibitors by employing PLATO, our target fishing and bioactivity prediction platform. Based on this rationale, we prepared RHE-334 and EA-11 and successfully tested their anti-proliferative potential against MCF-7 human breast cancer cells with IC50 values of 26.78±4.02 and 38.73±3.84 µM, respectively. Their toxicities were instead challenged against the WI-38. Interestingly, expression studies indicated that, in the presence of RHE-334, VEGFR-2 was equal to 0.52±0.03, thus comparable to imatinib equal to 0.63±0.03. In conclusion, this workflow based on theoretical and experimental approaches demonstrates effective in identifying VEGFR-2 inhibitors and can be easily adapted to other medicinal chemistry goals.

Advances in the Chemistry and Biology of Specialised Pro-Resolving Mediators (SPMs)

This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.