Break MKB, Ansari SA, Katamesh AA
… +3 more, Albadari N, Alshammari MD, Alkahtani HM
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40396612
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A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC = 3.11 µM). The com...A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC = 3.11 µM). The compound was less toxic towards normal MRC5 cells and exhibited ∼5-fold selectivity towards most cancer cells. CFSB caused G1-phase arrest, induced caspase-dependent apoptosis by increasing Bax/Bcl2 ratio and reduced metastasis by decreasing MMP9 in HepG2. Furthermore, CFSB was inactive against CDK2, EGFR, TrkA and VEGFR, but it strongly inhibited topoisomerase II (IC = 20 µM) with potency comparable to etoposide (IC = 15 µM), while weak inhibition was observed against tubulin (IC = 76 µM). DFT calculations revealed that CFSB had desirable reactivity, while docking indicated high binding affinity with topoisomerase II. Molecular dynamics and MM-GBSA analyses showed that CFSB-topoisomerase II complex was stable with favourable binding energies, while ADMET studies showed drug-like properties for CFSB.
Liu M, Zhao L, Huang X
… +12 more, Tang Z, Zhong Y, Yan M, Liu S, Wang S, Sun Z, Rao Z, Yu L, Fang Y, Zhang W, Zhang H, Peng W
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40396609
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The COVID-19 pandemic underscores the urgent need to develop broad-spectrum antivirals against coronaviruses (CoVs) to prepare for future outbreaks. In this study, we presented a systematic approach to developing broad-s...The COVID-19 pandemic underscores the urgent need to develop broad-spectrum antivirals against coronaviruses (CoVs) to prepare for future outbreaks. In this study, we presented a systematic approach to developing broad-spectrum M inhibitors, with a focus on high-risk CoVs. We optimised as a lead compound, with the goal of enhancing conserved interactions within the S1, S2, and S3/S4 pockets of M, leading to significantly improved inhibitory potency against representative CoVs. Compound exhibited submicromolar activity across all ten CoVs, with IC values below 0.1 μM for six of them. The X-ray co-crystal structure of SARS-CoV-2 M in complex with compound revealed the structural basis of conserved interactions contributing to its broad-spectrum activity. This study demonstrates the feasibility of reinforcing conserved interactions to develop M inhibitors with broad-spectrum activity and provides valuable strategies for combating future pandemics caused by unknown CoVs.
Lu Y, Partleton D, Gugu FM
… +6 more, Alhejaili AYG, Norris S, Harburn JJ, Gill JH, Sellars JD, Brown AK
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40396606
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Despite efforts to discover effective treatments to eradicate tuberculosis (TB), it remains a global threat. The increase in drug-resistant bacterial species has made the discovery of new drugs highly coveted. The utilis...Despite efforts to discover effective treatments to eradicate tuberculosis (TB), it remains a global threat. The increase in drug-resistant bacterial species has made the discovery of new drugs highly coveted. The utilisation of previous efficacious structures is one approach that can be employed to developing novel series of compounds to combat this ever-growing problem. This study sought to re-examine two such compounds, isoxyl (ISO) and SQ109, previously shown to be efficacious in TB treatment. SQ109-ISO hybrid compounds were shown to have demonstrable activity against both drug-sensitive and drug-resistant whilst displaying limited toxicity in comparison to other antitubercular agents. Indications from our genetic and biochemical studies suggest that these structurally similar pharmacophores bind to different proteins within , highlighting the need for careful consideration when producing regioisomeric analogues and that the utilisation of previous efficacious structures is a valid approach to developing promising novel drugs against .
Tian M, Zhao L, Lan Y
… +3 more, Li C, Ling Y, Zhou B
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40375621
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We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities . Cytotoxicity...We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities . Cytotoxicity tests were performed on three cell lines (DU145, T24, and HepG2) and a human normal cell line (HK-2). The half-inhibitory concentration (IC) of derivative UD-4c to hepatoma HepG2 cells (IC = 4.66 ± 0.12 μM) was significantly lower than that of sorafenib (IC =7.76 ± 0.12 μM), and exhibited less toxicity to HK-2 cells. Preliminary studies on the mechanism revealed that the derivative UD-4c could significantly inhibit the HepG2 cell growth and colony formation, block the HepG2 cell cycle in the G2/M phase, and induce apoptosis of HepG2 cells dose-dependently. The derivative UD-4c can be used as a potential lead compound to further develop new drugs for hepatocellular carcinoma treatment based on the evaluation of anti-cancer activity.
Zhang DW, Xu XS, Xie L
… +4 more, Xu L, Fu Z, Li Y, Xu X
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40371698
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The nucleocapsid protein (NP) of SARS-CoV-2, an RNA-binding protein, is capable of undergoing liquid-liquid phase separation (LLPS) during viral infection, which plays a crucial role in virus assembly, replication, and i...The nucleocapsid protein (NP) of SARS-CoV-2, an RNA-binding protein, is capable of undergoing liquid-liquid phase separation (LLPS) during viral infection, which plays a crucial role in virus assembly, replication, and immune regulation. In this study, we developed a homogeneous time-resolved fluorescence (HTRF) method for identifying inhibitors of the SARS-CoV-2 NP-RNA interaction. Using this HTRF-based approach, we identified two natural products, sennoside A and sennoside B, as effective blockers of this interaction. Bio-layer interferometry assays confirmed that both sennosides directly bind to the NP, with binding sites located within the C-terminal domain. Additionally, fluorescence recovery after photobleaching (FRAP) experiments revealed that sennoside B significantly inhibited RNA-induced LLPS of the NP, while sennoside A displayed comparatively weaker activity. Thus, the developed HTRF-based assay is a valuable tool for identifying novel compounds that disrupt the RNA-binding activity and LLPS of the SARS-CoV-2 NP. Our findings may facilitate the development of antiviral drugs targeting SARS-CoV-2 NP.
He Y, Xu H, Tan S
… +10 more, Long J, Lei H, Xiao L, Qi X, Deng M, Xiong X, You J, Zhu L, Lü M, Liang S
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40371697
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Type 2 diabetes mellitus (T2DM) and cancers are two globally prevalent diseases which can increase the incidence of each other. Intestinal α-glucosidase and β-glucuronidase are key targets for glycaemic control and chemo...Type 2 diabetes mellitus (T2DM) and cancers are two globally prevalent diseases which can increase the incidence of each other. Intestinal α-glucosidase and β-glucuronidase are key targets for glycaemic control and chemotherapy detoxification, respectively. This study first found that the leaf methanol extract of displayed dual inhibition to the two enzymes. The dually active constituents were then isolated and identified as two prenylated isoflavones of 6,8-diprenylorobol and 6,8-diprenylgenistein. Diprenylorobol exhibits competitive inhibition to both the two enzymes with values of 21.6 μM (α-glucosidase) and 1.41 μM (β-glucuronidase). Diprenylgenistein is an uncompetitive inhibitor of α-glucosidase ( = 11.4 μM) but a competitive inhibitor of β-glucuronidase ( = 1.69 μM). Molecular docking studies showed that both the two isoflavones tightly bind into the active pockets via various hydrogen bonds and hydrophobic interactions. In summary, the current study identifies two promising dual inhibitors of α-glucosidase and β-glucuronidase from the leaves of .
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40302183
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Liquidambaric acid, a pentacyclic triterpenoid from , was evaluated as a novel α-glucosidase inhibitor for type 2 diabetes mellitus (T2DM) management. Enzyme kinetic assays revealed its potent non-competitive inhibition...Liquidambaric acid, a pentacyclic triterpenoid from , was evaluated as a novel α-glucosidase inhibitor for type 2 diabetes mellitus (T2DM) management. Enzyme kinetic assays revealed its potent non-competitive inhibition (IC = 0.12 mM). Molecular docking showed stable hydrogen bonding at an allosteric site, altering enzyme conformation, while 100 ns molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complex. , a hyperglycaemic model demonstrated significant glucose reduction, confirming its hypoglycaemic potential. ADMET analysis predicted favourable bioavailability and low toxicity, supporting its development as a safe therapeutic agent. These findings integrate enzyme kinetics, molecular modelling, MD simulations, and validation, highlighting liquidambaric acid's potential as a multifunctional and cost-effective agent for T2DM management.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40302176
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2,5-dihydroxyacetophenone, a natural product from the fruiting bodies of , can effectively and safely inhibit the production of melanin in zebrafish model. To achieve analogues with more significant inhibition, 9 analogs...2,5-dihydroxyacetophenone, a natural product from the fruiting bodies of , can effectively and safely inhibit the production of melanin in zebrafish model. To achieve analogues with more significant inhibition, 9 analogs were synthesised and 13 analogues were purchased commercially. Among them, 14 compounds can inhibit melanin production, of which 5 compounds displayed the most significant inhibitory effects, with inhibitory rates of more than 80%, compared to positive control SymWhite377 (phenylethyl resorcinol). This study elucidated the melanin-inhibitory effects of 2,5-dihydroxyacetophenone and its analogs, providing a theoretical foundation for their potential applications in anti-melanogenic reagents.
Jaichand V, Lanrewaju AA, Baijnath H
… +2 more, Sabiu S, Mohanlall V
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40302171
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spp. has been traditionally used to manage type 2 diabetes mellitus, but the mechanisms and metabolites remain unclear. This study evaluated the inhibitory potential of Momordica extracts on α-amylase and α-glucosidase...spp. has been traditionally used to manage type 2 diabetes mellitus, but the mechanisms and metabolites remain unclear. This study evaluated the inhibitory potential of Momordica extracts on α-amylase and α-glucosidase , identifying cucurbitacin I and momordin Ic via high-performance liquid chromatography-photo diode array, and their inhibitory potential . Ethyl acetate seed extract (14.46 µg/ml) and hexane fruit flesh extract (16.79 µg/ml) exhibited lower IC values against α-amylase and α-glucosidase, respectively, compared to acarbose (reference standard). Comparatively, momordin Ic concentrations (36.57-605.98 µg/ml) were higher than cucurbitacin I (17.08-44.34 µg/ml). A 140 ns simulation showed that cucurbitacin I (-63.06 kcal/mol) and momordin Ic (-66.53 kcal/mol) exhibited stronger binding to α-amylase than acarbose (-36.46 kcal/mol), whereas cucurbitacin I (-38.08 kcal/mol) and momordin Ic (-54.87 kcal/mol) displayed weaker binding to α-glucosidase, relative to acarbose (-63.73 kcal/mol). Generally, momordin Ic demonstrated better thermodynamic properties, hence further and studies are needed to validate their antidiabetic potential.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40298145
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Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking....Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.
Sharma R, Mishra A, Bhardwaj M
… +5 more, Singh G, Indira Harahap LV, Vanjani S, Pan CH, Nepali K
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40256842
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This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase DNA-PK) in the DNA damage response (DDR) and their implications...This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.
Wang S, Li F, Feng X
… +5 more, Feng M, Niu X, Jiang X, Chen W, Bai R
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40213810
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Skin ageing is a complex physiological process primarily characterised by the deepening of wrinkles and the sagging of the skin. Collagen is essential for maintaining skin elasticity and firmness. As skin ages, it experi...Skin ageing is a complex physiological process primarily characterised by the deepening of wrinkles and the sagging of the skin. Collagen is essential for maintaining skin elasticity and firmness. As skin ages, it experiences structural and functional changes in collagen, including a decrease in collagen synthesis and an increase in collagen hydrolysis. Thus, promoting collagen synthesis represents a practical strategy for mitigating skin ageing. This review systematically described the functions, classifications and biosynthesis process of collagen, as well as its role in skin ageing. Additionally, the major signalling pathways and targets associated with collagen synthesis were also discussed. More importantly, the review provided a detailed summary of natural products with collagen synthesis-promoting effects and highlighted small molecule compounds with potential anti-ageing activity, especially PPARδ agonists. The relevant content offers potential targets and lead compounds for the development of anti-skin ageing therapies.
Mu J, Chen SS, Li SQ
… +3 more, Jin Q, Geng J, Zou LW
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40207794
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ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study,...ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.
Jiang Q, Zhong H, Wu C
… +7 more, Li J, Chen J, Zhou X, Li B, Yu H, Wang W, Sheng W
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40197120
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Xuetongsu (XTS, Schisanlactone E) is one of the main active compounds and considered as the star molecule isolated from (Roxb.) Craib. In order to improve XTS anti-tumour bioactivities, a series of novel XTS derivatives...Xuetongsu (XTS, Schisanlactone E) is one of the main active compounds and considered as the star molecule isolated from (Roxb.) Craib. In order to improve XTS anti-tumour bioactivities, a series of novel XTS derivatives were designed and synthesised by introducing an amide bond at the parent. Anti-proliferative assays on four different human tumour cell lines (BGC-823, HepG-2, HCT-116, and MCF-7) showed that the anti-tumour activities of most derivatives increased greatly compared to the parent XTS, and especially, compounds -, -, and - exhibited multiple anti-tumour effects. Among them, compound - has the best biological activities on the four tumour cell lines with the IC values ranging from 13.86 to 20.71 μM, which could significantly increase the fraction of apoptotic cells according to flow cytometry experience. Further study demonstrated that - could induce apoptosis on HepG-2 cells through influencing the key apoptotic related proteins, such as Bcl-2, Bax, and cleaved Caspase-3.
Luo Y, Peng Z, Tang J
… +3 more, Wang D, Tao S, Liu J
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40197056
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A series of kojic acid triazol thiosemicarbazide Schiff base derivatives were designed and synthesised. Evaluation on the inhibition of tyrosinase activity showed that these compounds possessed potent inhibit tyrosinase...A series of kojic acid triazol thiosemicarbazide Schiff base derivatives were designed and synthesised. Evaluation on the inhibition of tyrosinase activity showed that these compounds possessed potent inhibit tyrosinase activity, and the compound (IC = 0.94 μM) exhibited the best inhibitory effect. Preliminary structure-activity relationships indicate that steric hindrance, halogen atom radius, and electron donating ability of functional groups have some impact on the inhibition of tyrosinase activity. Inhibition mechanism showed that compound is a non-competitive mixed inhibitor, and this result was further confirmed by molecular docking. The fluorescence quenching mode of compound is dynamic quenching, and interacts with tyrosinase by changing the amide structure of tyrosinase. Compound has some anti-browning effect. Compound had the strongest DPPH radical scavenging activity (IC = 10.53 ± 0.014 μM), and compound showed the best ABTS scavenging activity (IC = 3.03 ± 0.009 μM).
Santoro AM, Persico M, D'Urso A
… +10 more, Cunsolo A, Tkachuk O, Milardi D, Purrello R, Tundo GR, Sbardella D, Osmulski PA, Gaczynska M, Coletta M, Fattorusso C
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40192126
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Decreased proteasome activity is a hallmark of brain and retinal neurodegenerative diseases (Alzheimer's, Parkinson's diseases, glaucoma) boosting the search for molecules acting as proteasome activators. Based on the hy...Decreased proteasome activity is a hallmark of brain and retinal neurodegenerative diseases (Alzheimer's, Parkinson's diseases, glaucoma) boosting the search for molecules acting as proteasome activators. Based on the hypothesis of an electrostatic key code driving catalytic core particle (20S) activation by regulatory particles (RPs), we identified the tetra-anionic meso-Tetrakis(4-sulphonatophenyl)-porphyrin (H2TPPS) as a new activator of human proteasome. By means of an integrated approach, including bioinformatics, enzymatic kinetic analysis, atomic force microscopy, and dynamic docking simulations, we show how binding of H2TPPS affects the closed/open conformational equilibrium of human 20S to ultimately promote substrate gate opening and proteolytic activity. These outcomes support our hypothesis and pave the way to the rational discovery of new proteasome allosteric modulators able to reproduce the key structural elements of regulatory particles responsible for catalytic activation.
Zhang D, Zhao J, Yang Y
… +5 more, Dai Q, Zhang N, Mi Z, Hu Q, Liu X
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40172117
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Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Alth...Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Although the first through third generations of EGFR tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy, the emergence of drug resistance continues to pose a challenge. Current research is now focused on fourth-generation EGFR-TKIs, which specifically target the EGFR harbouring the C797S mutation. This review examines the design strategies, antitumor activity both and , binding modes, pharmacokinetics, as well as the advantages and disadvantages of each inhibitor, alongside the progress of clinical stage research related to fourth-generation inhibitors. Additionally, the review discusses future development directions for fourth-generation EGFR-TKIs, aiming to provide insights for successful research and development in this field.
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40172115
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Steroidal compounds have emerged as effective therapeutic agents in oncology. Beyond natural-occurring and synthetic steroids that act as cytotoxic anti-tumoral agents, steroidal derivatives can be designed to mime the e...Steroidal compounds have emerged as effective therapeutic agents in oncology. Beyond natural-occurring and synthetic steroids that act as cytotoxic anti-tumoral agents, steroidal derivatives can be designed to mime the endogenous substrates of key metabolic enzymes in steroidogenesis, thus reducing the circulating levels of relevant oestrogenic and androgenic hormones responsible for cancer survival and proliferation. Therefore, enzyme inhibition represents an intriguing endocrine approach for the treatment of hormone-dependent tumours, such as breast and prostate cancer, with well-known approved drugs and several -clinical and clinical candidates under investigation. This review summarises the key advancements over the past decade (2014-2024) in the development of steroidal enzyme inhibitors endowed with anticancer activity, illustrating their mechanisms of action, therapeutic potential, drug design approaches, and current clinical applications. Furthermore, we discuss challenges related to drug resistance, off-target effects, and future strategies to optimise their efficacy in oncology.
Xu Z, Guan L, Wang Y
… +4 more, Niu MM, Ruan Y, Xu C, Yang L
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40052927
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PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the tr...PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the treatment of prostate cancer. Here, we identified five compounds (Hits 1-5) targeting the kinase domain (KD) of PLK1 using a combined virtual screening approach. Hits 1-5 all had picomolar (pM) inhibitory potency against PLK1. Notably, Hit-4 showed the strongest inhibitory activity against PLK1 (IC = 22.61 ± 1.12 pM) and displayed high selectivity for PLK1. Meanwhile, molecular dynamics (MD) simulations revealed that the complex formed by Hit-4 and PLK1 remained stable. Importantly, Hit-4 exhibited potent inhibitory effects on the proliferation of DU-145 prostate cancer cells (IC = 0.09 ± 0.01 nM). In conclusion, Hit-4 is a potent and highly selective antitumor candidate with therapeutic potential for prostate cancer.
El-Wakil MH, Ghazala RA, El-Dershaby HA
… +7 more, Drozdowska D, Wróbel-Tałałaj A, Parzych C, Ratkiewicz A, Kolesińska B, Abd El-Razik HA, Soliman FSG
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 40035286
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In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (DHFR). Fourteen new arylidene-hydrazinyl-...In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (DHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles () were synthesised and their dual DNA groove binding potential and DHFR inhibition were performed. Two compounds, and , proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed for and on MCF-7 cells using as reference. IC measurements revealed that both compounds were more potent and selective than . Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimisation and development.