Molecular Design Research Articles

Investigating the Precise Identification of Citrullination Sites with High-Performance Score Metrics using a Powerful Computation Predicting Tool.

To elucidate the detailed mechanisms of citrullination at the molecular level and design drugs applicable to major human diseases, predicting protein citrullination sites (PCSs) is essential. Using experimental approaches to predict PCSs is time-consuming and costly. However, there is a limited scope of the current PCS predictors. In particular, most predictors are commonly used for PCS prediction and have limited performance scores. This work aims to provide an improved sophisticated predictor of citrullination sites using a benchmark dataset in a machine learning platform. This study presents a reliable citrullination site predictor based on a benchmark dataset containing a 1:1 ratio of positive and negative samples. We classified citrullination sites using the Composition of the K-Spaced Amino Acid Pairs (CKSAAP) and Support Vector Machine (SVM). We developed PCS predictors using integrated machine-learning methods that produced the highest average scores. Using 10-fold cross-validation on test datasets, the True Positive Rate (TPR) was 98.34%, the True Negative Rate (TNR) was 99.44%, the accuracy was 98.89%, the Mathew Correlation Coefficient (MCC) was 98.21%, the Area Under the ROC Curve (AUC) was 0.999, and the partial Area Under the ROC Curve (pAUC) was 0.1968. According to overall performance, our developed predictor has a significantly higher implementation in comparison with the current tools on the same benchmark dataset. Moreover, it showed better performance metrics on both test and training datasets. Our developed predictor is promising and can be implemented as a complementary technique for identifying fast and precise citrullination sites.

Enhancement of Efficiency of Perovskite Solar Cells with Hole-Selective Layers of Rationally Designed Thiazolo[5,4-d]thiazole Derivatives.

We introduce thiazolo[5,4-d]thiazole (TT)-based derivatives featuring carbazole, phenothiazine, or triphenylamine donor units as hole-selective materials to enhance the performance of wide-bandgap perovskite solar cells (PSCs). The optoelectronic properties of the materials underwent thorough evaluation and were substantially fine-tuned through deliberate molecular design. Time-of-flight hole mobility TTs ranged from 4.33 × 10-5 to 1.63 × 10-3 cm2 V-1 s-1 (at an electric field of 1.6 × 105 V cm-1). Their ionization potentials ranged from -4.93 to -5.59 eV. Using density functional theory (DFT) calculations, it has been demonstrated that S0 → S1 transitions in TTs with carbazolyl or ditert-butyl-phenothiazinyl substituents are characterized by local excitation (LE). Mixed intramolecular charge transfer (ICT) and LE occurred for compounds containing ditert-butyl carbazolyl-, dimethoxy carbazolyl-, or alkoxy-substituted triphenylamino donor moieties. The selected derivatives of TT were used for the preparation of hole-selective layers (HSL) in PSC with the structure of glass/ITO/HSLs/Cs0.18FA0.82Pb(I0.8Br0.2)3/PEAI/PC61BM/BCP/Ag. The alkoxy-substituted triphenylamino containing TT (TTP-DPA) has been demonstrated to be an effective material for HSL. Its layer also functioned well as an interlayer, improving the surface of control HSL_2PACz (i.e., reducing the surface energy of 2PACz from 66.9 to 52.4 mN m-1), thus enabling precise control over perovskite growth energy level alignment and carrier extraction/transportation at the hole-selecting contact of PSCs. 2PACz/TTP-DPA-based devices showed an optimized performance of 19.1 and 37.0% under 1-sun and 3000 K LED (1000 lx) illuminations, respectively. These values represent improvements over those achieved by bare 2PACz-based devices, which attained efficiencies of 17.4 and 32.2%, respectively. These findings highlight the promising potential of TTs for the enhancement of the efficiencies of PSCs.

Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated in vitro and in vivo. Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities in vitro against four tested phytopathogenic fungi, including Fusarium graminearum, Botrytis cinerea, Sclerotinia sclerotiorum, and Rhizoctonia solani. Especially, compound 5aa displayed a broad spectrum of antifungal activity against F. graminearum, B. cinerea, S. sclerotiorum, and R. solani, with the corresponding EC50 values of 0.12, 4.48, 0.33, and 0.15 μg/mL, respectively. In the antifungal growth assay, compound 5aa displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 μg/mL. In another in vivo antifungal activity evaluation, compound 5aa exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 μg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound 5aa has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound 5aa might cause mycelial abnormalities and organelle damage in F. graminearum. Moreover, in the in vitro enzyme assay, we found that the target compounds 5aa, 5ab, and 5ca displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC50 values of 1.62, 1.74, and 1.96 μM, respectively, which were superior to that of boscalid (IC50 = 2.38 μM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds 5aa, 5ab, and 5ca have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.

Novel PEO-based Solid Polymer Electrolyte with High Elasticity and High Ionic Conductivity for Room Temperature Lithium Metal Batteries

Abstract The development and application of polyethylene oxide (PEO) based solid polymer electrolyte (SPE) is severely constrained by its low ionic conductivity and poor tensile resistance. To improve the electrochemical performance of SPE without losing its mechanical properties, a benzene sulfonate-based additive is adopted into crosslinking system composed of -CH2-CH2-O- segments to obtain a membrane with a high ionic conductivity of 1.47×10-4 S cm-1 and an ionic transference number of 0.70 at room temperature. The activation energy value of 0.128 eV gives evidence for a favorable migration mechanism of PTH-SPE. Anti-dendrite growth and contact optimization can be realized by molecular structure design with a tensile elongation of 490%. The reversible overpotential of Li||Li symmetric cell within 1000 h demonstrates that the compact PTH-SPE can inhibit the growth of lithium dendrite. This work provides a new strategy for designing high-performance solid electrolytes for room temperature via a green solvent-free method.

Recent advances in tunable solid-state emission based on α-cyanodiarylethenes: from molecular packing regulation to functional development.

The design and development of organic solid-state luminescent materials stand as crucial pillars within the realm of contemporary photofunctional materials. Overcoming challenges such as concentration quenching and achieving tailored luminescent properties necessitates a judicious approach to molecular structure design and the strategic utilization of diverse stimuli to modulate molecular packing patterns. Among the myriad candidates, α-cyanodiarylethenes (CAEs) emerge with distinctive solid-state luminescent attributes, capable of forming self-assembled packing structures with varying degrees of π-π stacking. This characteristic endows them with potential in the field of intelligent molecular responsive materials and optoelectronic devices. This tutorial review embarks on an exploration of design strategies geared towards attaining tunable solid-state emission through customized packing of CAEs. It explores the utilization of stimuli responses, including such as mechanical forces, light irradiation, solvent interactions, thermal influences, as well as the utilization of co-assembly methodologies. The overarching aim of this review is to provide a widely applicable platform fostering the flourishing development of modern organic photofunctional materials through integrating principles of molecular engineering, organic optoelectronics, and materials science.

Stellane at the Forefront: Derivatization and Reactivity Studies of a Promising Saturated Bioisostere of ortho-Substituted Benzenes.

This work highlights stellane's cage stability and derivatization opportunities. A diverse range of building blocks were synthesized using modern synthesis protocols to demonstrate stellane's reactivity and chemical tolerance across different reaction systems, proving its promise as a bioisosteric scaffold. It can be utilized in scaffold-based molecular design and is superior in terms of topological precision compared to existing ortho isosteres, as well as monosubstituted benzene mimetics, holding the potential to become a robust platform for future medicinal chemistry studies.

Self-assembly of discrete multi-chromophoric systems.

Self-assembly of chromophoric systems is a prerequisite to create well-ordered, processable nanomaterials with multiple functionalities. In the past two decades, the field of functional organic materials has primarily focused on systems featuring only one type of dye/π-conjugated unit. Consequently, many reports with mechanistic insights on the self-assembly of the dyes featuring different molecular packing have been reported. Subsequently, we have witnessed several attempts to organize the multi-chromophoric systems in solution and solid-state via different approaches using self-assembly as a tool. Incorporation of more than one dye is important in creating materials with tuneable optoelectronic properties. Consequently, self-assembly of more than one chromophoric systems have been investigated to some extent. This review aims to discuss the self-assembled materials derived from discrete π-conjugated systems comprising more than one dye units connected through covalent bonding (multi-chromophoric systems). Molecular design of various multi-chromophoric systems leading to the formation of crystals, liquid crystals and supramolecular polymers have been correlated with corresponding properties. We envisage that classification of self-assembled multi-chromophoric systems, with a note on tuneable optoelectronic properties, can provide a deeper understanding on the molecular design strategies, which is important in the fabrication of functional organic materials with optimum performances.

X-LoRA: Mixture of low-rank adapter experts, a flexible framework for large language models with applications in protein mechanics and molecular design

We report a mixture of expert strategy to create fine-tuned large language models using a deep layer-wise token-level approach based on low-rank adaptation (LoRA). Starting with a set of pre-trained LoRA adapters, our gating strategy uses the hidden states to dynamically mix adapted layers, allowing the resulting X-LoRA model to draw upon different capabilities and create never-before-used deep layer-wise combinations to solve tasks. The design is inspired by the biological principles of universality and diversity, where neural network building blocks are reused in different hierarchical manifestations. Hence, the X-LoRA model can be easily implemented for any existing large language model without a need for modifications of the underlying structure. We develop a tailored X-LoRA model that offers scientific capabilities, including forward/inverse analysis tasks and enhanced reasoning capability, focused on biomaterial analysis, protein mechanics, and design. The impact of this work includes access to readily expandable and adaptable models with strong domain knowledge and the capability to integrate across areas of knowledge. Featuring experts in biology, mathematics, reasoning, bio-inspired materials, mechanics and materials, chemistry, protein biophysics, mechanics, and quantum-mechanics based molecular properties, we conduct a series of physics-focused case studies. We examine knowledge recall, protein mechanics forward/inverse tasks, protein design, adversarial agentic modeling including ontological knowledge graph construction, and molecular design. The model is capable not only of making quantitative predictions of nanomechanical properties of proteins or quantum mechanical molecular properties but also reasoning over the results and correctly predicting likely mechanisms that explain distinct molecular behaviors.

Lithium-Ion Dynamic and Storage of Atomically Precise Halogenated Nanographene Assemblies via Bottom-Up Chemical Synthesis.

Graphene has received much scientific attention as an electrode material for lithium-ion batteries because of its extraordinary physical and electrical properties. However, the lack of structural control and restacking issues have hindered its application as carbon-based anode materials for next generation lithium-ion batteries. To improve its performance, several modification approaches such as edge-functionalization and electron-donating/withdrawing substitution have been considered as promising strategies. In addition, group 7A elements have been recognized as critical elements due to their electronegativity and electron-withdrawing character, which are able to further improve the electronic and structural properties of materials. Herein, we elucidated the chemistry of nanographenes with edge-substituted group 7A elements as lithium-ion battery anodes. The halogenated nanographenes were synthesized via bottom-up organic synthesis to ensure the structural control. Our study reveals that the presence of halogens on the edge of nanographenes not only tunes the structural and electronic properties but also impacts the material stability, reactivity, and Li+ storage capability. Further systematic spectroscopic studies indicate that the charge polarization caused by halogen atoms could regulate the Li+ transport, charge transfer energy, and charge storage behavior in nanographenes. Overall, this study provides a new molecular design for nanographene anodes aiming for next-generation lithium-ion batteries.

Tuning thermoelectric performance with N-annulated perylene-based small molecules and single-walled carbon nanotube nanocomposite films

Two N-annulated perylene (NP)-based organic small molecules (OSMs) with end groups of di-p-tolylamine (DTA) and phenyl-di-p-tolylamine (PhDTA), namely DDTANP and DPhDTANP, are incorporated into single-walled carbon nanotubes (SWCNTs) to fabricate nanocomposite thin films for thermoelectric (TE) application. The weight ratios of OSMs to SWCNTs range from 1:1 to 1:4. The inherent planar structures of these novel OSMs facilitate strong π-π interactions and charge transfer with SWCNTs. Specifically, the DDTANP/SWCNT nanocomposite films, due to its lower HOMO, induces pronounced energy filtering and, thus, a high Seebeck coefficient (S). At the optimized weight ratio of 1:3, DDTANP/SWCNT nanocomposite thin film exhibits an electrical conductivity (σ) of 214.7 S cm−1, and S of 59.8 μV K−1. The flat structure of DPhDTANP enhances its adhesion to SWCNTs, thereby improving dispersion and increasing σ. Similarly, the DPhDTANP/SWCNT (1:3) nanocomposite thin film achieves 256.4 S cm−1, and an S of 55.8 μV K−1. The DPhDTANP/SWCNT (1:3) nanocomposite film exhibits higher σ, resulting in a power factor (PF) of 79.8 μW m−1 K−2, surpassing the PF of 76.7 μW m−1 K−2 for the DDTANP/SWCNT (1:3) nanocomposite film. These findings offer valuable insights into molecular design for SWCNTs-based composite TE research and contributed to enhancing TE applications.

Development of scoring-assisted generative exploration (SAGE) and its application to dual inhibitor design for acetylcholinesterase and monoamine oxidase B

De novo molecular design is the process of searching chemical space for drug-like molecules with desired properties, and deep learning has been recognized as a promising solution. In this study, I developed an effective computational method called Scoring-Assisted Generative Exploration (SAGE) to enhance chemical diversity and property optimization through virtual synthesis simulation, the generation of bridged bicyclic rings, and multiple scoring models for drug-likeness. In six protein targets, SAGE generated molecules with high scores within reasonable numbers of steps by optimizing target specificity without a constraint and even with multiple constraints such as synthetic accessibility, solubility, and metabolic stability. Furthermore, I suggested a top-ranked molecule with SAGE as dual inhibitors of acetylcholinesterase and monoamine oxidase B through multiple desired property optimization. Therefore, SAGE can generate molecules with desired properties by optimizing multiple properties simultaneously, indicating the importance of de novo design strategies in the future of drug discovery and development.Scientific contribution The scientific contribution of this study lies in the development of the Scoring-Assisted Generative Exploration (SAGE) method, a novel computational approach that significantly enhances de novo molecular design. SAGE uniquely integrates virtual synthesis simulation, the generation of complex bridged bicyclic rings, and multiple scoring models to optimize drug-like properties comprehensively. By efficiently generating molecules that meet a broad spectrum of pharmacological criteria—including target specificity, synthetic accessibility, solubility, and metabolic stability—within a reasonable number of steps, SAGE represents a substantial advancement over traditional methods. Additionally, the application of SAGE to discover dual inhibitors for acetylcholinesterase and monoamine oxidase B not only demonstrates its potential to streamline and enhance the drug development process but also highlights its capacity to create more effective and precisely targeted therapies. This study emphasizes the critical and evolving role of de novo design strategies in reshaping the future of drug discovery and development, providing promising avenues for innovative therapeutic discoveries.

Molecular Design and Organic Photovoltaic Applications of Carboxylate‐Functionalized P‐type Polymers

Molecular Design and Organic Photovoltaic Applications of Carboxylate‐Functionalized P‐type Polymers

Mismatched Supramolecular Interactions Facilitate the Reprocessing of Super-Strong and Ultratough Thermoset Elastomers.

Thermoset elastomers have been extensively applied in many fields because of their excellent mechanical strengths and durable characteristics, such as an excellent chemical resistance. However, in the context of environmental issues, the nonrecyclability of thermosets has become a major barrier to the further development of these materials. Here, a well-tailored strategy is reported to solve this problem by introducing mismatched supramolecular interactions (MMSIs) into a covalently cross-linked poly(urethane-urea) network with dynamic acylsemicarbazide moieties. The MMSIs significantly strengthen and toughen the thermoset elastomer by effectively dissipating energy and resisting external stress. In addition, the elastomer recycling efficiency is improved 2.7-fold due to the superior reversibility of the MMSIs. The optimized thermoset elastomerfeatures outstanding characteristics, including an ultrahigh tensile strength (110.8MPa), an unprecedented tensile toughness (1245.2MJ m-3), as well as remarkable resistance to chemical media, creep, and damage. Most importantly, it exhibits an extraordinary multirecyclability, and the 4th recycling efficiency remains close to 100%. This scalable method promotes the development of thermosets with both high performance and excellent recyclability, thereby providing valuable guidance for addressing the issue of nonrecyclability from a molecular design standpoint.

Molecular Design of Pyrene and Its Derivatives to Make Microcrystalline Films with Silver Luster Effect Using Drop-Casting Method

Molecular Design of Pyrene and Its Derivatives to Make Microcrystalline Films with Silver Luster Effect Using Drop-Casting Method

Molecular Generation, QSAR, and Molecular Dynamic Simulation Studies for Virtual Screening of DNA Polymerase Theta Inhibitors.

The machine learning-based QSAR modeling procedure, molecular generations, and molecular dynamic simulations were applied to virtually screen the DNA polymerase theta inhibitors. The DNA polymerase theta (Polθ or POLQ) is an attractive target for treatments of homologous recombination deficient (such as BRCA deficient) cancers. There are no approved drugs for targeting POLQ, and only one inhibitor is in Phase Ⅱclinical trials; thus, it is necessary to develop novel POLQ inhibitors. To build machine learning models that predict the bioactivities of POLQ inhibitors. To build molecular generation models that generate diverse molecules. To virtually screen the generated molecules by the machine learning models. To analyze the binding modes of the screening results by molecular dynamic simulations. In the present work, 325 inhibitors with POLQ polymerase domain bioactivities were Collected. Two machine learning methods, random forest and deep neural network, were used for building the ligand- and structure-based quantitative structure-activity relationship (QSAR) models. The substructure replacement-based method and transfer learning-based deep recurrent neural network method were used for molecular generations. Molecular docking and consensus QSAR models were carried out for virtual screening. The molecular dynamic simulations and MM/GBSA binding free energy calculation and decomposition were used to further analyze the screening results. The MCC values of the best ligand- and structure-based consensus QSAR models reached 0.651 and 0.361 for the test set, respectively. The machine learning-based docking scores had better-predicted ability to distinguish the highly and weakly active poses than the original docking scores. The 96490 molecules were generated by both molecular generation methods, and 10 molecules were retained by virtual screening. Four favorable interactions were concluded by molecular dynamic simulations. We hope that the screening results and the binding modes are helpful for designing the highly active POLQ polymerase inhibitors and the models of the molecular design workflow can be used as reliable tools for drug design.

A Systematic Study of Methyl Carbodithioate Esters as Effective Gold Contact Groups for Single‐Molecule Electronics

There are several binding groups used within molecular electronics for anchoring molecules to metal electrodes (e.g., R–SMe, R–NH2, R–CS2−, R–S−). However, some anchoring groups that bind strongly to electrodes have poor/unknown stability, some have weak electrode coupling, while for some their binding motifs are not well defined. Further binding groups are required to aid molecular design and to achieve a suitable balance in performance across a range of properties. We present an in‐depth investigation into the use of carbodithioate esters as contact groups for single‐molecule conductance measurements, using scanning tunnelling microscopy break junction measurements (STM‐BJ) and detailed surface spectroscopic analysis. We demonstrate that the methyl carbodithioate ester acts as an effective contact for gold electrodes in STM‐BJ measurements. Surface enhanced Raman measurements demonstrate that the C=S functionality remains intact when adsorbed on to gold nanoparticles. A gold(I) complex was also synthesised showing a stable C=Sׄ→AuI interaction from the ester. Comparison with a benzyl thiomethyl ether demonstrates that the C=S moiety significantly contributes to charge transport in single‐molecule junctions. The overall performance of the CS2Me group demonstrates it should be used more extensively and has strong potential for the fabrication of larger area devices with long‐term stability.

Triphenylamine[3]arenes: Streamlining Synthesis of a Versatile Macrocyclic Platform for Supramolecular Architectures and Functionalities.

Triphenylamine[3]arenes (TPA[3]s), featuring [16]paracyclophane backbone with alternating carbon and nitrogen bridging atoms, were synthesized through a BF3·Et2O-catalyzed cyclization reaction using triphenylamine derivatized monomers and paraformaldehyde. This molecular design yielded a series of TPA[3] macrocycles with high efficiency, with their facile derivatizations also successfully demonstrated. On account of the strong electron-donating properties of the TPA moieties, these TPA[3]s exhibit remarkable delayed fluorescence, and possess a significant affinity for iodine. Furthermore, their inherent three-fold symmetry rendered TPA[3]s as novel building blocks for the construction of extended frameworks and molecular cages. This advancement expands the versatility of discrete macrocycles into complex architectures, enhancing their applicability across a broad spectrum of applications.

A Systematic Study of Methyl Carbodithioate Esters as Effective Gold Contact Groups for Single-Molecule Electronics.

There are several binding groups used within molecular electronics for anchoring molecules to metal electrodes (e.g., R-SMe, R-NH2, R-CS2-, R-S-). However, some anchoring groups that bind strongly to electrodes have poor/unknown stability, some have weak electrode coupling, while for some their binding motifs are not well defined. Further binding groups are required to aid molecular design and to achieve a suitable balance in performance across a range of properties. We present an in-depth investigation into the use of carbodithioate esters as contact groups for single-molecule conductance measurements, using scanning tunnelling microscopy break junction measurements (STM-BJ) and detailed surface spectroscopic analysis. We demonstrate that the methyl carbodithioate ester acts as an effective contact for gold electrodes in STM-BJ measurements. Surface enhanced Raman measurements demonstrate that the C=S functionality remains intact when adsorbed on to gold nanoparticles. A gold(I) complex was also synthesised showing a stable C=Sׄ→AuI interaction from the ester. Comparison with a benzyl thiomethyl ether demonstrates that the C=S moiety significantly contributes to charge transport in single-molecule junctions. The overall performance of the CS2Me group demonstrates it should be used more extensively and has strong potential for the fabrication of larger area devices with long-term stability.

Triphenylamine[3]arenes: Streamlining Synthesis of a Versatile Macrocyclic Platform for Supramolecular Architectures and Functionalities

Triphenylamine[3]arenes (TPA[3]s), featuring [16]paracyclophane backbone with alternating carbon and nitrogen bridging atoms, were synthesized through a BF3·Et2O‐catalyzed cyclization reaction using triphenylamine derivatized monomers and paraformaldehyde. This molecular design yielded a series of TPA[3] macrocycles with high efficiency, with their facile derivatizations also successfully demonstrated. On account of the strong electron‐donating properties of the TPA moieties, these TPA[3]s exhibit remarkable delayed fluorescence, and possess a significant affinity for iodine. Furthermore, their inherent three‐fold symmetry rendered TPA[3]s as novel building blocks for the construction of extended frameworks and molecular cages. This advancement expands the versatility of discrete macrocycles into complex architectures, enhancing their applicability across a broad spectrum of applications.

Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα: Dynophore-derived discovery

The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.