Structure-activity Relationship Research Articles

A Review on Indole as a Cardinal Scaffold for Anticancer Drugs Development

Abstract: Chemotherapy is the mainstay of therapeutic cancer therapy; however, the development of resistance typically makes it less effective. There are continuous efforts by researchers to find novel lead compounds with potent anti-cancer activity. Generally, synthetic or natural heterocyclic compounds have been investigated in detail as a scaffold for cancer therapeutics. Among them, indole, owing to its unique physiochemical and biological properties, provides a promising platform for the development of pharmacophores for drug development against cancer, acting via various mechanisms. Till now, several indole-based derivatives have been identified as anti-cancer agents, which are either being used in clinics or are in various phases of clinical trials, suggesting their importance in anti-cancer drug development. These anti-cancer drugs have been classified into different classes depending on their mechanism of action. For example, histone deacetylase inhibitors (HDAC inhibitors), silent mating type information regulation 2 homolog (SIRT) inhibitors, tubulin inhibitors, proviral insertion site in Moloney murine leukemia virus (Pim) inhibitors, DNA Topoisomerase inhibitors, and kinase inhibitors. In this review, the author's approach is to compile the recent developments on indole-based anti-cancer drugs and provide insight into the respective structureactivity relationships (SARs) of the compounds. We hope the review will provide a thorough understanding to the reader and guide to developing novel and potent indole-based anticancer agents against drug-sensitive and drug-resistant cancer in the future.

Insight into the Synthesis, Biological Activity, and Structure-activity Relationship of 1,2,4-Oxadiazole and Analogs: A Comprehensive Review

Abstract: A five-membered heterocyclic compound known as 1,2,4-oxadiazole has one oxygen, two carbon, and two nitrogen atoms within a ring. Numerous studies have shown that 1,2,4-oxadiazole has the potential to be an essential moiety in many harmful pharmacological conditions. 1,2,4-oxadiazole and its derivatives have been used as an antiviral, cough suppressant, vasodilator, anxiolytic, etc. To synthesize a single molecule with potent pharmacological action, two or more pharmacophores are combined currently. This enhances pharmacological effects, facilitates interaction possible with many targets, and reduces the adverse effects related to them. It has been reported that synthesis of 1,2,4-oxadiazole and its analog is possible using a variety of methods. In this present review, we emphasized recently accepted synthetic methods for 1,2,4-oxadiazole and its analogs synthesis. Additionally, the structure-activity relationship concerning several pharmacological effects, interactions with various targets, and the utility of different techniques for the analysis and purification has been described. On the behalf of the above study, the researchers can use this review study to better understand their 1,2,4-oxadiazole research in the future.

Thiazolidinedione as a Promising Medicinal Scaffold for the Treatment of Type 2 Diabetes.

Thiazolidinediones, also known as glitazones, are considered as biologically active scaffold and a well-established class of anti-diabetic agents for the treatment of type 2 diabetes mellitus. Thiazolidinediones act by reducing insulin resistance through elevated peripheral glucose disposal and glucose production. These molecules activate peroxisome proliferated activated receptor (PPARγ), one of the sub-types of PPARs, and a diverse group of its hybrid have also shown numerous therapeutic activities along with antidiabetic activity. The objective of this review was to collect and summarize the research related to the medicinal potential, structure-activity relationship and safety aspects of thiazolidinedione analogues designed and investigated in type 2 diabetes during the last two decades. The mentioned objective was achieved by collecting and reviewing the research manuscripts, review articles, and patents from PubMed, Science Direct, Embase, google scholar and journals related to the topic from different publishers like Wiley, Springer, Elsevier, Taylor and Francis, Indian and International government patent sites etc. Results: The thiazolidinedione scaffold has been a focus of research in the design and synthesis of novel derivatives for the management of type 2 diabetes, specifically in the case of insulin resistance. The complications like fluid retention, idiosyncratic hepatotoxicity, weight gain and congestive heart failure in the case of trosiglitazone, and pioglitazone have restricted their use. The newer analogues have been synthesized by different research groups to attain better efficacy and less side effects. Thus, the potential of thiazolidinediones in terms of their chemical evolution, action on nuclear receptors, aldose reductase and free fatty acid receptor 1 is well established. The newer TZD analogues with better safety profiles and tolerability will soon be available in the market for common use without further delay.

Heparin Oligosaccharides as Vasoactive Intestinal Peptide Inhibitors via their Binding Process Characterization.

It has been proven that vasoactive intestinal peptide (VIP) was involved in the pathogenesis of prostate cancer. Cardin et al. found that by an alanine scan, the heparin- binding site on VIP was exactly the same sequence in VIP and its receptor. Therefore, heparin could competitively block the binding of VIP and its receptor. However, the structure-activity relationship between heparin and VIP has not been reported, especially in terms of the sequence and sulfation patterns of heparin oligosaccharides upon binding to VIP. A variety of experiments were designed to study the binding process and structure-activity relationship between heparin oligosaccharides and VIP. Heparin was enzymatically digested and purified to produce heparin oligosaccharides, and the structures were characterized by NMR. The binding capacity between heparin oligosaccharides and VIP was analyzed by GMSA and ITC experiments. The binding between heparin oligosaccharides and VIP was simulated using a molecular docking program to show the complex. ELISA assay was used to investigate the effect of non-anticoagulant heparin oligosaccharides on the VIP-mediated cAMP/PKA signaling pathway in vitro. The results indicated that both the length and the sulfation pattern of heparin oligosaccharides affected its binding to VIP. VIP could induce the expression of cAMP at a higher level in PC3 cells, which could be regulated by the interaction of heparin oligosaccharides and VIP. The binding between heparin oligosaccharides and VIP could block the binding between VIP and its receptor on tumor cells. Downloading the regulation of the expression level of cAMP could possibly further affect the subsequent activation of PKA. These non-anticoagulant heparin oligosaccharides may block the VIP-mediated cAMP/PKA signaling pathway and thus exert their antitumor activity.

Research progress in Estrogen-related receptor gamma (ERRγ) agonists and inverse agonists.

Estrogen-related receptor gamma (ERRγ), one of three members of the ERR family, is an inducible transcription factor. ERRγ has dual functions in different tissues. The decreased expression of ERRγ in the brain, stomach, prostate, and fat cells can cause neuropsychological dysfunction, gastric cancer, prostate cancer, and obesity. However, when ERRγ is present in the liver, pancreas, and thyroid follicular cells, ERRγ overexpression is related to liver cancer, type II diabetes, oxidative liver injury, and anaplastic thyroid carcinoma. Signaling pathway studies have confirmed that ERRγ agonists or inverse agonists can regulate ERRγ expression to treat related diseases. The collision between residue Phe435 and the modulator is a key factor determining the activation or inhibition of ERRγ. Although more than 20 agonists and inverse agonists of ERRγ have been reported, no clinical studies have been found in the literature. This review summarizes the important relationship between ERRγ-related signaling pathways and diseases, research progress, and the structure-activity relationship of modulators. These findings provide guidance for further study on new ERRγ modulators.

Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage-gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions.

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.

Bridged Pt-OH-Mn Mediator in N-coordinated Mn Single Atoms and Pt Nanoparticles for Electrochemical Biomolecule Oxidation and Discrimination.

The rational design of efficient catalysts for uric acid (UA) electrooxidation, as well as the establishment of structure-activity relationships, remains a critical bottleneck in the field of electrochemical sensing. To address these challenges, herein, a hybrid catalyst that integrates carbon-supported Pt nanoparticles and nitrogen-coordinated Mn single atoms (PtNPs/MnNC) is developed. The metal-metal interaction during annealing affords the construction of metallic-bonded Pt-Mn pairs between PtNPs and Mn single atoms, facilitating the electron transfer from PtNPs to the support and thereby optimizing the electronic structure of catalysts. More importantly, experiments and theoretical calculations provide visual proof for the 'incipient hydrous oxide adatom mediator' mechanism for UA oxidation. The Pt-Mn pairs first adsorb OH* to construct the bridged Pt-OH-Mn mediators to serve as a highly active intermediate for N-H bond dissociation and proton transfer. Benefiting from the unique electronic and geometric structure of the catalytic center and reactive intermediates, PtNPs/MnNC exhibits superior electrooxidation performance. The electrochemical sensor based on PtNPs/MnNC enables sensitive detection and discrimination of UA and dopamine in serum samples. This work offers new insights into the construction of novel electrocatalysts for sensitive sensing platforms.

Chemical Design Strategy of Ionizable Lipids for In Vivo mRNA Delivery.

Lipid nanoparticles (LNPs) are the most clinically successful drug delivery systems that have accelerated the development of mRNA drugs and vaccines. Among various structural components of LNPs, more recent attention has been paid in ionizable lipids (ILs) that was supposed as the key component in determining the effectiveness of LNPs for in vivo mRNA delivery. ILs are typically comprised of three moieties including ionizable heads, linkers, and hydrophobic tails, which suggested that the combination of different functional groups in three moieties could produce ILs with diverse chemical structures and biological identities. In this concept article, we provide a summary of chemical design strategy for high-performing IL candidates and discuss their structure-activity relationships for shifting tissue-selective mRNA delivery. We also propose an outlook for the development of next-generation ILs, enabling the broader translation of mRNA formulated with LNPs.

Total Synthesis of (-)-Piericone D.

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective β-O-glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.

Isolation, derivatization, and anti-microbial evaluation of secondary metabolites from Garcinia dryobalanoides

A detailed study on secondary metabolites from the stem bark of Garcinia dryobalanoides has yielded one triterpenoid and four xanthones. Along with that, five novel rubraxanthone derivatives had been successfully synthesised via Williamson etherification with various alkyl halides. The antibacterial evaluation on crude extract, isolated secondary metabolites (1-5), and synthesised compounds (6-9) against Lactiplantibacillus plantarum, Enterobacter cloacae, Pseudomonas aeruginosa, and Serratia marcescens demonstrated moderate to active activities outlining their bacteriostatic potential. The structure-activity relationship (SAR) study conducted revealed the presence of prenyl and hydroxy groups on the xanthone attributed to good bacterial inhibition. The introduction of the alkyl chain to the hydroxy part eventually decreases the antibacterial activity of the compound which is probably due to the bulkiness that causes steric hindrances, therefore limiting the ability to bind to its target site within the bacterial cell.

Targeted discovery of unusual diterpenoids with anti-fungal activity from the root of Euphorbia lathyris

Lathyrisone A (1), a diterpene with an undescribed tricyclic 6/6/6 fused carbon skeleton, along with spirolathyrisins B-D (3–5), three diterpenes with a rare [4.5.0] spirocyclic carbon skeleton, and one known compound (2) were isolated from the roots of Euphorbia lathyris. Their chemical structures were characterized by extensive spectroscopic analysis, X-ray crystallography, ECD and quantum chemistry calculation. A plausible biosynthetic pathway for compounds 1–5 was proposed, which suggested it is a competitive pathway for ingenol biosynthesis in the plant. The anti-fungal activities of these compounds were tested, especially, compound 2 showed stronger anti-fungal activities against Fusarium oxysporum and Alternaria alternata than the positive control fungicide thiophanate-methyl. The preliminary structure–activity relationship of compounds 1–5 was also discussed. These results not only expanded the chemical diversities of E. lathyris, but also provided a lead compound for the control of plant pathogens.

Structural characteristics and anti-tumor effect of low molecular weight Dendrobium officinale polysaccharides by reconstructing tumor microenvironment

In this study, glucanase and mannanase were selected to hydrolysis DOP to obtain low molecular weight DOP (LMWDOP), namely glucanase-hydrolysis Dendrobium officinale polysaccharides (GDOP) and mannanase-hydrolysis Dendrobium officinale polysaccharides (MDOP). The antitumor activity of LMWDOPs and its effect on tumor immune microenvironment were investigated. The growth of transplantable S180 sarcoma in mice was significantly inhibited by GDOP, and MDOP in a dose-dependent manner compared with the model group (P < 0.05, P < 0.01). This indicated that mannanase-hydrolysis Dendrobium officinale polysaccharides have stronger anti-tumor activity. The structure of MDOP was systematically characterized to explore the structure–activity relationship. The average molecular weight of MDOP was 3494 Da. MDOP had a linear chain structure consisting mainly of →6)-α-d-Glcp-(1→ and →4)-β-d-Manp-(1 → residues. O-acetyl group linked to C2 of →4)-β-d-Manp-(1 → residue. In conclusion, it has been determined that the small molecule dendrobium polysaccharides obtained from the hydrolysis of mannanase have good anti-tumor activity and can reconstruct the immune microenvironment. “→ 6-α-d-Glcp- (1 → 4)-β-d-Manp-(1→) may be the structural basis for Dendrobium officinale polysaccharides to exert anti-tumor effects.

Real-Time Direct Monitoring of Chirality Fixation and Recognition at the Single-Molecule Level.

Chirality, a fundamental attribute of nature, significantly influences a wide range of phenomena related to physical properties, chemical reactions, biological pharmacology, and so on. As a pivotal aspect of chirality research, chirality recognition contributes to the synthesis of complex chiral products from simple chiral compounds and exhibits intricate interplay between chiral materials. However, macroscopic detection technologies cannot unveil the dynamic process and intrinsic mechanisms of single-molecule chirality recognition. Herein, we present a single-molecule detection platform based on graphene-molecule-graphene single-molecule junctions to measure the chirality recognition involving interactions between amines and chiral alcohols. This approach leads to the realization of in situ and real-time direct observation of chirality recognition at the single-molecule level, demonstrating that chiral alcohols exhibit compelling potential to induce the formation of the corresponding chiral configuration of molecules. The amalgamation of theoretical analyses with experimental findings reveals a synergistic action between electrostatic interactions and steric hindrance effects in the chirality recognition process, thus substantiating the microscopic mechanism governing the chiral structure-activity relationship. These studies open up a pathway for exploring novel chiral phenomena from the fundamental limits of chemistry, such as chiral origin and chiral amplification, and offer important insights into the precise synthesis of chiral materials.

Progressive Optimization of Lanthanide Nanoparticle Scintillators for Enhanced Triple‐Activated Radioluminescence Imaging

AbstractLanthanide nanoparticle (LnNP) scintillators exhibit huge potential in achieving radionuclide‐activated luminescence (radioluminescence, RL). However, their structure–activity relationship remains largely unexplored. Herein, progressive optimization of LnNP scintillators is presented to unveil their structure‐dependent RL property and enhance their RL output efficiency. Benefiting from the favorable host matrix and the luminescence‐protective effect of core–shell engineering, NaGdF4 : 15 %Eu@NaLuF4 nanoparticle scintillators with tailored structures emerged as the top candidates. Living imaging experiments based on optimal LnNP scintillators validated the feasibility of laser‐free continuous RL activated by clinical radiopharmaceuticals for tumor multiplex visualization. This research provides unprecedented insights into the rational design of LnNP scintillators, which would enable efficient energy conversion from Cerenkov luminescence, γ‐radiation, and β‐electrons into visible photon signals, thus establishing a robust nanotechnology‐aided approach for tumor‐directed radio‐phototheranostics.

Experimental insights and modeling innovations: Deciphering Fe(VI) oxidation in imidazole ionic liquids through QSAR and RFR

In this investigation, we conducted a detailed analysis of the oxidation of 16 imidazole ionic liquid variants by Fe(VI) under uniform experimental setups, thereby securing a dataset of second-order reaction rate constants (kobs). This methodology ensures superior data consistency and comparability over traditional methods that amalgamate disparate data from varied studies. Utilizing 16 chemical structural parameters obtained via Density Functional Theory (DFT) as descriptors, we developed a Quantitative Structure Activity Relationship (QSAR) model. Through rigorous correlation analysis, Principal Component Analysis (PCA), Multiple Linear Regression (MLR), and Applicability Domain (AD) evaluation, we identified a pronounced negative correlation between the molecular orbital gap energy (Egap) and kobs. MLR analysis further underscored Egap as a pivotal predictive variable, with its lower values indicating heightened oxidative reactivity towards Fe(VI) in the ionic liquids, leading the QSAR model to achieve a predictive accuracy of 0.95. Furthermore, we integrated an advanced machine learning approach - Random Forest Regression (RFR), which adeptly highlighted the critical factors influencing the oxidation efficiency of imidazole ionic liquids by Fe(VI) through elaborate decision trees, feature importance assessment, Recursive Feature Elimination (RFE), and cross-validation strategies. The RFR model demonstrated a remarkable predictive performance of 0.98. Both QSAR and RFR models pinpointed Egap as a key descriptor significantly affecting oxidation efficiency, with the RFR model presenting lower root mean square errors, establishing it as a more reliable predictive tool. The application of the RFR model in this study significantly improved the model's stability and the intuitive display of key influencing factors, introducing promising advanced analytical tools to the field of environmental chemistry.

Progressive Optimization of Lanthanide Nanoparticle Scintillators for Enhanced Triple-Activated Radioluminescence Imaging.

Lanthanide nanoparticle (LnNP) scintillators exhibit huge potential in achieving radionuclide-activated luminescence (radioluminescence, RL). However, their structure-activity relationship remains largely unexplored. Herein, progressive optimization of LnNP scintillators is presented to unveil their structure-dependent RL property and enhance their RL output efficiency. Benefiting from the favorable host matrix and the luminescence-protective effect of core-shell engineering, NaGdF4 : 15 %Eu@NaLuF4 nanoparticle scintillators with tailored structures emerged as the top candidates. Living imaging experiments based on optimal LnNP scintillators validated the feasibility of laser-free continuous RL activated by clinical radiopharmaceuticals for tumor multiplex visualization. This research provides unprecedented insights into the rational design of LnNP scintillators, which would enable efficient energy conversion from Cerenkov luminescence, γ-radiation, and β-electrons into visible photon signals, thus establishing a robust nanotechnology-aided approach for tumor-directed radio-phototheranostics.

Anticancer Potential of the S-Heterocyclic Ring Containing Drugs and its Bioactivation to Reactive Metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i. e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

Task-Similarity is a Crucial Factor for Few-Shot Meta-Learning of Structure-Activity Relationships.

Machine learning models support computer-aided molecular design and compound optimization. However, the initial phases of drug discovery often face a scarcity of training data for these models. Meta-learning has emerged as a potentially promising strategy, harnessing the wealth of structure-activity data available for known targets to facilitate efficient few-shot model training for the specific target of interest. In this study, we assessed the effectiveness of two different meta-learning methods, namely model-agnostic meta-learning (MAML) and adaptive deep kernel fitting (ADKF), specifically in the regression setting. We investigated how factors such as dataset size and the similarity of training tasks impact predictability. The results indicate that ADKF significantly outperformed both MAML and a single-task baseline model on the inhibition data. However, the performance of ADKF varied across different test tasks. Our findings suggest that considerable enhancements in performance can be anticipated primarily when the task of interest is similar to the tasks incorporated in the meta-learning process.

Fluorescent small molecule donors.

Small molecule donors (SMDs) play subtle roles in the signaling mechanism and disease treatments. While many excellent SMDs have been developed, dosage control, targeted delivery, spatiotemporal feedback, as well as the efficiency evaluation of small molecules are still key challenges. Accordingly, fluorescent small molecule donors (FSMDs) have emerged to meet these challenges. FSMDs enable controllable release and non-invasive real-time monitoring, providing significant advantages for drug development and clinical diagnosis. Integration of FSMDs with chemotherapeutic, photodynamic or photothermal properties can take full advantage of each mode to enhance therapeutic efficacy. Given the remarkable properties and the thriving development of FSMDs, we believe a review is needed to summarize the design, triggering strategies and tracking mechanisms of FSMDs. With this review, we compiled FSMDs for most small molecules (nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, reactive oxygen species and formaldehyde), and discuss recent progress concerning their molecular design, structural classification, mechanisms of generation, triggered release, structure-activity relationships, and the fluorescence response mechanism. Firstly, from the large number of fluorescent small molecular donors available, we have organized the common structures for producing different types of small molecules, providing a general strategy for the development of FSMDs. Secondly, we have classified FSMDs in terms of the respective donor types and fluorophore structures. Thirdly, we discuss the mechanisms and factors associated with the controlled release of small molecules and the regulation of the fluorescence responses, from which universal guidelines for optical properties and structure rearrangement were established, mainly involving light-controlled, enzyme-activated, reactive oxygen species-triggered, biothiol-triggered, single-electron reduction, click chemistry, and other triggering mechanisms. Fourthly, representative applications of FSMDs for trackable release, and evaluation monitoring, as well as for visible in vivo treatment are outlined, to illustrate the potential of FSMDs in drug screening and precision medicine. Finally, we discuss the opportunities and remaining challenges for the development of FSMDs for practical and clinical applications, which we anticipate will stimulate the attention of researchers in the diverse fields of chemistry, pharmacology, chemical biology and clinical chemistry. With this review, we hope to impart new understanding thereby enabling the rapid development of the next generation of FSMDs.