Nitrogen-containing heterocycles constitute the core of many approved drugs and clinical candidates, making efficient and predictable C-N bond construction a central objetive in medicinal chemistry. Aliphatic azo compounds, traditionally employed as radical initiators, have recently emerged as versatile programmable nitrogen donors, capable of transferring their nitrogen atoms directly into heterocyclic scaffolds. This review summarizes advances in the reactivity of azoaliphatic derivatives with alkynes, highlighting pathways where nitrogen atoms are retained in the final products and on their implications for drug delivery. Cycloaddition processes provide rapid access to privileged heterocycles such as pyrazoles and pyrroles, scaffolds that are well represented in marketed drugs and support early structure-activity relationship exploration. Complementary radical and carbenoid manifolds enable the formation of hydrazides, atropisomeric frameworks and rarer nitrogen-sulfur motifs, offering increased three-dimensionality and new vectors for tuning potency, selectivity and pharmacokinetic properties. Where available, representative case studies illustrate how these scaffolds have contributed to lead optimization, target selectivity or progression toward clinical evaluation. Beyond reactivity, this review critically evaluates scalability, operational robustness and sustainability to define when azo-alkyne methodologies are realistically applicable in medicinal chemistry workflows. Rather than presenting azo compounds as general-purpose reagents, we frame them as strategic nitrogen donors whose reactivity can be aligned with specific stages of the drug discovery pipeline. When used in this manner, azo-alkyne transformations enable efficient scaffold generation, late-stage diversification and access to underexplored chemical space relevant to modern medicinal chemistry.

Cyanoacrylamides as versatile scaffolds in medicinal chemistry: From synthetic strategies to therapeutic applications

Medicinal chemistry advances of SGLT inhibitors: SAR, structural innovation, and mechanistic insights.

PROTACs as novel therapeutics against Mycobacterium tuberculosis: Current progress and future directions.

Carboranes are chemically and biologically stable boron‑carbon clusters with promising applications in medicinal chemistry. While their use in boron neutron capture therapy (BNCT) has been extensively explored, recent attention has shifted toward understanding their interactions with biological macromolecules, particularly proteins. Here, we characterize the interaction between closo-ortho-carborane and lysozyme (LSZ) using NMR spectroscopy, molecular docking and molecular dynamics simulations, and enzymatic assays. Experimental data demonstrate that carborane forms a stable 1:1 complex with LSZ (Carborane@LSZ), retaining the monomeric state and the protein fold, with only a limited number of amino acids involved in the interaction. In particular, NMR chemical shift perturbations revealed specific binding near the substrate-binding pocket, a result corroborated by molecular docking and molecular dynamic simulations. Carborane fits into a hydrophobic pocket near the substrate-binding site, where the recognition process is driven by hydrophobic interactions complemented by classical hydrogen and non-standard dihydrogen bonding. Carborane-@LSZ complex partially inhibits enzymatic activity (∼33%). Extending this approach to bovine serum albumin (BSA) revealed similar binding principles, underscoring the generality of carborane-protein supramolecular interactions. These findings provide fundamental insights into pristine carboranes recognition by proteins and establish a foundation for designing carborane-based therapeutics and delivery platforms in nanomedicine.

Biochemical effects and theoretical study of a metformin in the carp (Cyprinus carpio) fry.

Asymmetric Fe-N3C coordination in Fe single-atom sites boosts electrochemical activation of H2O2 for efficient •OH generation.

Xanthine oxidase inhibitors for gout: Applications and novel drug development.

ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality-A paradigm shift in Cancer therapy.

Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma.

Overexpression of MERTK and FLT3 plays a crucial role in activating signal transduction pathways in various human hematological malignancies. These signaling pathways have been extensively studied and have shown significant potential as a promising therapeutic target for the treatment of acute myeloid leukemia (AML). In this study, we employed a modern medicinal chemistry approach, hybridizing machine learning (ML) with a bioisosterism strategy, to design and synthesize a new series of pyrrolo[2,3-d] pyridine derivatives as potent dual inhibitors of MERTK and FLT3. Through successive structure-activity relationship (SAR) studies, we successfully identified the lead compound 31l as a highly potent and selective MERTK/FLT3 dual inhibitor. Compound 31l exhibited remarkable kinase inhibitory activity against MERTK and FLT3 with IC50 values of 2.58 and 0.86 nM, respectively, and potential anti-proliferative activity against MOLM-13 cell lines (IC50 value of 7.50 nM). Furthermore, compound 31l displayed a favorable metabolic stability profile in both human and mouse liver microsome screens and an oral bioavailability of 56%. This finding suggests that lead compound 31l is a promising tool for further optimization and development as a potential MERTK/FLT3 dual inhibitor anti-AML drug candidate.

Therapeutic targeting of CDK12: a medicinal chemistry perspective.

Quinic acid (QA) is a natural product recognized for its potential in medicinal chemistry. While traditionally studied as a structural moiety of chlorogenic acids, QA and synthetic derivatives thereof are becoming more relevant as independent scaffolds with broad therapeutic relevance. This review highlights the growing body of work on their biological activities, including anti-inflammatory, antibacterial, and anticancer effects, as well as their roles in metabolic and immune modulation. Chemically, QA offers a rich framework for structural modification, enabling the design of diverse molecules with improved properties for drug development. Several derivatives have shown promising results in preclinical models, and new synthetic strategies continue to expand their applicability. By focusing on QA itself, instead of its more commonly studied esters, this review underscores its emerging value as a versatile and underutilized scaffold.

Stereoisomers arising from the rotational restriction about a CN single bond, namely CN atropisomers, have recently attracted considerable attention in the field of synthetic organic chemistry. Diverse CN atropisomeric compounds have been prepared with high optical purity through catalytic enantioselective reactions, and they have been used in various asymmetric reactions as chiral building blocks and chiral ligands. CN atropisomers are attractive compounds from the viewpoint of not only synthetic organic chemistry but also medicinal chemistry. Recently, various CN atropisomeric bioactive compounds have been found, and their biological activity, the target selectivity, and the pharmacokinetics have been revealed to differ significantly between atropisomers. On the other hand, we feel that the chemistry community is still not fully aware of the fascinating biological properties of CN atropisomers. This review article comprehensively describes CN atropisomeric compounds exhibiting diverse biological activities as well as the synthesis or separation of atropisomers and their rotational stability.

Cyclobutenes are found in natural products and medicinal chemistry and can be readily functionalized. Herein is presented a straightforward, transition-metal-free [2 + 2] cycloaddition reaction of readily available ynimines with N,N-dimethyl cinnamamides to access fully substituted cyclobutenes. It is proposed that the ynimine is deprotonated, and the resulting allenyl anion undergoes conjugate addition to the cinnamamide followed by ring closure to afford the cyclobutene products. This reaction has good scope, proceeds in 40-83% yield, and is atom economical.

A facile and efficient DBU-mediated [3 + 3] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with diazo esters for the synthesis of trifluoromethyl dihydro-1,2,4-triazine-spirooxindole derivatives has been developed. The reaction proceeds under mild conditions with a broad substrate scope, tolerating various electronically and sterically diverse substituents to afford moderate to excellent yields. Furthermore, a one-pot cycloaddition/oxidation strategy is established to achieve efficient synthesis of trifluoromethyl-1,2,4-triazine-spirooxindoles. This study not only enriches the structural diversity of spirooxindoles but also provides a valuable synthetic tool for developing novel bioactive molecules in medicinal chemistry.

Direct carbonyl desaturation to prepare α,β-unsaturated carbonyl compounds is an important area of research in organic synthesis owing to the significance of these molecules in medicinal chemistry and chemical biology. Despite numerous methods developed for this transformation, approaches that enable precise control over the site selectivity of the reaction on substrates containing multiple potential reactive sites remain rare, limiting their applications in late-stage functionalization of complex molecules. Here we report the engineering of 'ene'-reductases for the direct carbonyl desaturation of diverse cyclic ketones to their corresponding enones with excellent site divergence. This study leverages the distinctive ability of 'ene'-reductases to differentiate the stereochemical environments of hydrogens at the carbonyl β-positions. The synthetic utility of this biocatalytic platform is further demonstrated through the successful late-stage dehydrogenation on terpenoids with complementary site selectivity to existing methods. In addition, the method could efficiently prepare chiral enones with a β-all carbon quaternary stereogenic centre via biocatalytic desaturative kinetic resolution. Mechanistic studies elucidate key enzyme-substrate interactions responsible for the enzyme-controlled site divergence.

Here, we report the modular synthesis of trifluoromethylated/difluoromethylated dihydroquinoline sulfonyl fluorides via [4 + 2] cycloadditions of o-aminotrifluoroacetophenone derivatives or o-aminodifluoroacetophenone derivatives with 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF) under mild reaction conditions. Subsequent sulfur(VI) fluoride exchange was subjected to optimization for nucleophiles based on nitrogen and oxygen, furnishing sulfonamides and sulfonates, respectively. The reaction is accomplished without employing transition metal catalysts, yielding novel products that hold significant potential in the fields of medicinal chemistry, chemical biology, and drug discovery.

The replacement of aromatic rings with saturated molecular frameworks is a recent development encapsulated by the motto "escape from flatland" and conceptualized through the use of saturated benzene bioisosteres. This Review summarizes the application of the smallest bicyclic and spirocyclic ring systems as saturated scaffolds, focusing on applications in constructing bioactive molecules. We discuss considerations of their molecular strains, their potential to serve as saturated benzene isosteres in terms of both volume and geometry, and structural data derived from small-molecule and protein crystallography. Additionally, we present general approaches to synthesis, examine the current commercial availability of functional building blocks, and present existing examples of applications of bicyclic systems in drug discovery programs. At least eight structures based on the smallest skeletons have advanced to clinical trials, with one, vanzacaftor, recently receiving U.S. FDA approval. Our analysis indicates that small bicyclic fragments are represented exceptionally unevenly. While bicyclo[1.1.1]pentane and spiro[3.3]heptane have become routine and indispensable in medicinal chemistry over the past decade, ladderane and housane remain exotic and unexplored. We highlight knowledge gaps, aiming to stimulate interest in small saturated skeletons for innovative molecular engineering.

ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a panel of analogs of JPC0661 to establish structure-activity relationships and improve its in vivo efficacy by replacing its amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA in vitro and in vivo and suppresses ΔFOSB function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease neuropathology) leads to virtually complete loss of ΔFOSB bound to genomic DNA as detected by CUT&RUN sequencing. Our findings corroborate that the binding/release of AP1 transcription factors to DNA can be controlled via small molecules in vivo, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a much more efficacious inhibitor of ΔFOSB function in vivo. These findings define a strategy to design small-molecule inhibitors for other AP-1 and AP-1-related transcription factors, in particular, those involved in neuropsychiatric and neurological disorders.