Structure-activity Relationship Studies Research Articles

Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.

Selective and Orally Bioavailable c-Met PROTACs for the Treatment of c-Met-Addicted Cancer.

c-Met is an attractive therapeutic target in multiple tumors. Previous studies have discovered some effective proteolysis-targeting chimeras (PROTACs) able to degrade c-Met; however, the structure-activity relationship (SAR), degradation selectivity, and pharmacokinetic profiles of c-Met PROTACs have, to date, remained largely unknown. Herein, through extensive SAR studies on various warheads, linkers, and E3 ligase ligands, a novel potent c-Met PROTAC Met-DD4 was identified. Our results suggested that Met-DD4 could induce robust c-Met degradation with excellent selectivity (DC50 = 6.21 nM), substantially killing the c-Met-addicted cancer cells (IC50 = 4.37 nM). Furthermore, in vivo studies showed that Met-DD4 could achieve excellent oral bioavailability and c-Met degradation, strongly retarding tumor growth with minute organ toxicity. Overall, this study reveals that targeted degradation of c-Met is a promising strategy for the treatment of c-Met-addicted cancers and provides novel lead compounds for the clinical translation of c-Met PROTACs.

An 11-mer Synthetic Peptide Suppressing Aggregation of Aβ25-35 and Resolving Its Aggregated Form Improves Test Performance in an Aβ25-35-Induced Alzheimer's Mouse Model.

There is a high demand for the development of drugs against Alzheimer's disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), due to the increasing number of patients with AD. In our present study, we aimed to assess the aggregation inhibitory effect of various synthetic YS-peptides on Aβ25-35 to identify an applicable peptide for clinical use for AD treatment and prevention. Suppression and aggregate resolution activities of YS-peptides against Aβ25-35 were evaluated using a Thioflavin T assay and scanning electron microscopy (SEM). Structure-activity relationship studies revealed that YS-RD11 (RETLVYLTHLD) and YS-RE16 (RETLVYLTHLDYDDTE) showed suppression and aggregate-resolution activities. The effect of YS-peptides on phagocytosis in microglial cells (BV-2 cells) demonstrated that YS-RD11 and YS-RE16 activated the phagocytic ability of microglia. In the Aβ25-35-induced AD mouse model, YS-RD11 prevented and improved the deficits in short-term memory. In conclusion, YS-RD11 is a suitable candidate therapeutic drug against AD and uses a strategy similar to that used for antibodies.

Structure-Function Relationship of a Novel MTX-like Peptide (MTX1) Isolated and Characterized from the Venom of the Scorpion Maurus palmatus.

Maurotoxin (MTX) is a 34-residue peptide from Scorpio maurus venom. It is reticulated by four disulfide bridges with a unique arrangement compared to other scorpion toxins that target potassium (K+) channels. Structure-activity relationship studies have not been well performed for this toxin family. The screening of Scorpio maurus venom was performed by different steps of fractionation, followed by the ELISA test, using MTX antibodies, to isolate an MTX-like peptide. In vitro, in vivo and computational studies were performed to study the structure-activity relationship of the new isolated peptide. We isolated a new peptide designated MTX1, structurally related to MTX. It demonstrated toxicity on mice eight times more effectively than MTX. MTX1 blocks the Kv1.2 and Kv1.3 channels, expressed in Xenopus oocytes, with IC50 values of 0.26 and 180 nM, respectively. Moreover, MTX1 competitively interacts with both 125I-apamin (IC50 = 1.7 nM) and 125I-charybdotoxin (IC50 = 5 nM) for binding to rat brain synaptosomes. Despite its high sequence similarity (85%) to MTX, MTX1 exhibits a higher binding affinity towards the Kv1.2 and SKCa channels. Computational analysis highlights the significance of specific residues in the β-sheet region, particularly the R27, in enhancing the binding affinity of MTX1 towards the Kv1.2 and SKCa channels.

Computing Zagreb Connection Indices for the Cartesian Product of Path and Cycle Graphs

Topological indices ( ) are a class of graph-based descriptors widely used in chemiformatics and Quantitative Structure-Activity Relationship (QSAR) studies. TIs capture key structural features of molecules by encoding graph-theoretic information, offering a quantitative representation of molecular topology. Each mathematical network is associated with a specific numerical value determined by a function. Among the Zagreb connection indices have been extensively researched. This study delves into the Cartesian product of cycle graphs with path graphs, elucidating the comprehensive implications of . These indices encompass the first , second , and third . Furthermore, comprehensive results of the modified first , modified second , and modified third are presented, along with the first multiplicative ZCI second multiplicative ZCI (SMZCI), and third multiplicative ZCI Moreover, modified first multiplicative ZCI ), modified second multiplicative ZCI and modified third multiplicative ZCI ( are also calculated. To provide precision, both the graphical and numerical analyses of the computed findings are aligned for the two Cartesian products. The foundation for mathematically modeling complex networks and chemical structures lies in graph theory. Topological indices ( ) are a class of graph-based descriptors widely used in chemiformatics and quantitative structure-activity relationship (QSAR) studies. TIs capture key structural features of molecules by encoding graph-theoretic information, offering a quantitative representation of molecular topology. Each mathematical network is associated with a specific numerical value determined by a topological index function. Among these the Zagreb connection indices are extensively researched TIs. This article delves into the Cartesian product of cycle graphs with path graphs, elucidating the comprehensive implications of . These indices encompass the first, Second and third. Furthermore, we present the comprehensive results of the modified , modified and modified , and also present the first multiplicative Zagreb connection index , and , along with their modified counterparts like modified first multiplicative Zagreb connection index , and . These analysis encompass two distinct types of graphs: cycle graphs and path graphs. To provide further precision, we align both the graphical and numerical analysis of our computed findings for these two Cartesian products.

Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen.

NLRP3, a crucial member of the NLRP family, plays a pivotal role in immune regulation and inflammatory modulation. Here, we report a potent and specific NLRP3 inhibitor Z48 obtained though docking-based virtual screening and structure-activity relationship studies with an IC50 of 0.26 μM in THP-1 cells and 0.21 μM in mouse bone marrow-derived macrophages. Mechanistic studies indicated that Z48 could bind directly to the NLRP3 protein (KD = 1.05 μM), effectively blocking the assembly and activation of the NLRP3 inflammasome, consequently manifesting anti-inflammatory properties. Crucially, with acceptable mouse pharmacokinetic profiles, Z48 demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, while displaying no significant therapeutic impact on NLRP3KO mice. In conclusion, this study provided a promising NLRP3 inflammasome inhibitor with novel molecular scaffold, poised for further development as a therapeutic candidate in the treatment of inflammatory bowel disease.

Synthesis and biological studies of acetophenone-based novel chalcone, semicarbazone, thiosemicarbazone and indolone derivatives: Structure-Activity relationship, molecular docking, molecular dynamics, and kinetic studies

This study presents the synthesis and evaluation of nine acetophenone derivatives (1–9), with compounds 2, 4, 5, 6, 7, and 9 being novel and synthesized for the first time. These derivatives encompass diverse structural motifs including chalcone, thiosemicarbazone, semicarbazone, and indolone derivatives. The structures of synthesized compound were confirmed by NMR analysis. The synthesized compounds were assessed for their in vitro enzyme inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-Glycosidase enzymes, as well as their antioxidant capacities using the DPPH radical scavenging assay. With Ki values ranging from 8.96±0.40 to 44.16±4.25 nM, these showed effective inhibition of AChE. However, the inhibitory characteristics of all drugs were almost the same. The Ki values of the two most active compounds, (3) and (4), were 8.96±0.40 and 11.33±0.58 nM, respectively. Regarding α-Glycosidase, they demonstrate that all novel compounds (1–9) have IC50 values between 30.16 and 133.98 µM, whereas the Ki values vary from 42.71±5.90 to 128.78±8.03 µM. Compound 4 emerged as a notable inhibitor, displaying significant inhibition against all used enzymes. Molecular docking studies revealed its exceptional binding affinities, corroborated by MM-GBSA ΔG binding free energies, and Glide Emodel scores. Compound 7 also exhibited promising inhibitory potential against α-Glycosidase. Docking scores for hAChE -12.207, for hBChE -10.140 and for α-Glycosidase -10.590 kcal/mol. The 250 ns molecular dynamics simulations confirmed the stability of the ligand-protein complexes, particularly with compound 4. The ligand-protein complexes were found extremely stable according to the MD simulations. Additionally, ADME predictions indicated favorable pharmacokinetic properties and drug-likeness for all compounds, further supporting their potential as orally active agents. Compound 4, in particular, stands out as a multitarget drug candidate, with strong inhibition against key enzymes implicated in neurodegenerative diseases and diabetes, suggesting its therapeutic potential in these conditions.

Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design.

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics-ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies.

CETZOLE Analogs as Potent Ferroptosis Inducers and Their Target Identification Using Covalent/Affinity Probes.

Ferroptosis is a recently discovered cell death mechanism triggered by iron-dependent elevation of reactive oxygen species leading to lipid membrane peroxidation. We previously reported the development of a new class of ferroptosis inducers referred to as CETZOLEs with CC50 values in the low micromolar range. Structure-activity relationship study of these compounds led to the development of more potent analogs with CC50 values in the nanomolar range. Cells exposed to these compounds displayed the hallmarks of ferroptosis including cell death through ROS accumulation. Cancer cells were found to be more sensitive to these compounds than normal cells. Proteomic studies using covalent and affinity probes led to the identification of cystathionine β-synthase, peroxiredoxins, ADP/ATP carriers, and glucose dehydrogenase as enriched proteins. The binding of CETZOLEs to these proteins as well as GPX4 was validated by Western blotting. This group of proteins is known to be associated with cellular antioxidant pathways.

Structure-Activity Relationship Studies Leading to the Discovery of Highly Water-Soluble and Biocompatible Acyclic Cucurbit[n]uril FY-3451 as a Universal Antagonist That Rapidly Reverses Neuromuscular Blocking Agents In Vivo.

The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[n]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative acCB6 (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). In vivo experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, acCB6 can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.

WDR5 Binding to Histone Serotonylation Is Driven by an Edge-Face Aromatic Interaction with Unexpected Electrostatic Effects.

Histone serotonylation has emerged as a key post-translational modification. WDR5 preferentially binds to serotonylated histone 3 (H3), and this binding event has been associated with tumorigenesis. Herein, we utilize genetic code expansion, structure-activity relationship studies, and computation to study an edge-face aromatic interaction between WDR5 Phe149 and serotonin on H3 that is key to this protein-protein interaction. We find experimentally that this edge-face aromatic interaction is unaffected by modulating the electrostatics of the face component but is weakened by electron-withdrawing substituents on the edge component. Overall, these results elucidate that this interaction is governed by van der Waals forces as well as electrostatics of the edge ring, a result that clarifies discrepancies among previous theoretical models and model system studies of this interaction type. This is the first evaluation of the driving force of an edge-face aromatic interaction at a protein-protein interface and provides a key benchmark for the nature of these understudied interactions that are abundant in the proteome.

Machine learning approaches in designing anti-HIV nitroimidazoles: 2D/3D QSAR, kNN-MFA, docking, dynamics, PCA analysis and MMGBSA studies

In this study, newly synthesized 20 nitroimidazole derivatives were subjected to 2D and 3D Quantitative Structure-Activity Relationship (QSAR) study to investigate their anti-HIV activity against both ROD and IIIB strains. Later, proposed hypothesis was virtually proved by further in-silico studies. In statistically significant 2D-QSAR models r2 values for IIIB strains 0.9241 and for ROD strains 0.9412 with corresponding q2 values of 0.7706 and 0.8299, were obtained, respectively. Different models were constructed using three different kNN-MFA 3D QSAR approaches such as SW-FB, SA score, and GA. By using the generated hypothesis, newer analogues of nitroimidazole derivatives was designed and molecular modelling studies were conducted to prove the hypothesis. The three molecules were displayed the good docking scores compared to the reference molecule. The stabilities of docked complexes were analyzed by MD simulations and MMGB/SA calculations. These results offer insightful design guidance for novel anti-HIV compounds synthesis and suggest interesting directions for future pharmaceutical research.

Pyroptosis and chemical classification of pyroptotic agents.

Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.

Acyl Hydrazides as Insecticides: Synthesis, Biochemical, Structure-Activity Relationship Studies and Insecticidal Activity of some IGRs Analogues Against Spodoptera littorallis (Boisd.).

The exponential rise in pesticide resistance to conventional chemical pesticides is another major factor driving the development of novel insecticidal active agents. One approach to solving this problem is to investigate novel classes and environmentally safe insecticidal chemicals with a variety of modes of action. Among these techniques is the creation of novel tebufenozide derivatives. Tebufenozide belongs to the insect growth regulator class of insecticides and is regarded as one of the safest chemical insecticides ever. The toxicological and biochemical efficiency of each analog was assessed against the Spodoptera littoralis pest in both its second and fourth instar larvae. The bioassay results show that compound 7 was the most effective insecticidal agent, with LC50 values of 10.6.5 and 18.7 mg/L against S. littoralis larvae in their second and fourth instar larvae, respectively. Finally, it was shown how treatment with the LC50 of the examined substances affected the activity of many enzymes involved in the cuticle production of S. littoralis larvae in their fourth instar. From this study, it was concluded that Acyl hydrazide are helpful for the management of S. littoralis and will be an effective replacement for other synthetic insecticides.

Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3-d]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M4 and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3-d]pyrimidine tricycle core provided lead compound, VU6016235, with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

Exploring the Potential of Terpenoids as a Possible Treatment for Cancer: Structure-Activity Relationship and Mechanistic Studies.

Cancer stands as a significant global health challenge due to its mortality rates and the complexities involved in its treatment. Addressing issues, such as metastasis, recurrence, chemoresistance, and treatment-related toxicity, remains pivotal in cancer therapy advancement. Therefore, exploration of novel therapeutic agents has emerged as a priority. As the risk of cancer continues to rise, effective measures must be taken to combat it. One promising approach is to explore natural remedies, such as terpenoids, which have demonstrated anticancer activity. Utilizing terpenoids could aid in the development of potent compounds to fight cancer. By studying the structural makeup of various terpenoid derivatives from previous research, we can identify which structural groups are essential for their anticancer activity. This understanding of the structure-activity relationship is crucial for developing new, effective anticancer agents based on terpenoids. Terpenoids, a diverse class of plant-derived secondary metabolites composed of multiple isoprene units, have garnered attention for their potential anticancer and pharmacological qualities. Some terpenoids exhibit notable anticancer effects by concentrating on several stages of cancer development. They show promise in blocking the initiation of early carcinogenesis by the induction of cell cycle arrest, the inhibition of cancer cell differentiation, and the induction of apoptosis. This study delves into the investigation of specific terpenoids showcasing promising anticancer activity against prevalent malignancies, including breast, colon, ovarian, and lung cancers. The study also explores the relationship between the structure and activity of these compounds, which sheds light on how effective they are against a variety of cancer cell types. The comprehensive discussion centres on elucidating terpenoids with substantial potential for combating diverse cancer types, offering insights into their structural features and promising anticancer mechanisms.

Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 μM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.

Benzothiazole derivatives as effective α-glucosidase inhibitors: an insight study of structure-activity relationships and molecular targets

Benzothiazole derivatives as effective α-glucosidase inhibitors: an insight study of structure-activity relationships and molecular targets

Theoretical and experimental investigation on newly synthesized pyrazolopyridine derivatives: Insight into the compound activity, NLO response, and molecular dynamics

Pyrazolopyridine derivatives exhibiting biological activity are widely present in drug molecules. The title compound, ethyl 3-amino-6-methyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (II), was designed and synthesized and the structure characterized by spectroscopic techniques and confirmed by single-crystal X-ray diffraction. The pyrazolopyridine moiety is not quite planar and the thiophene and ester groups are rotated well out of the mean plane of the pyridine ring. N—H···N and C—H···O hydrogen bonds plus π-stacking interactions form thick layers of molecules parallel to (001). Based on structural activity relationship studies, II exhibits potent activity against fibroblast collagenase-1 complexed to a diphenyl-ether sulphone-based hydroxamic acid or Matrix Metalloproteinase (MMP-1). Theoretical simulations were performed to probe the reactivity and electronic properties of II where the quantum theory of atoms in molecules and NBO analysis was used to describe the bonding nature and charge transfer excitation. The optical and nonlinear characteristics of II are also evidenced by its hyperpolarizability response. The kinetic and thermodynamic stability of II was monitored through a computed ab-initio molecular dynamics study. In addition, a Hirshfeld surface analysis was performed to assess the intermolecular interactions. Efficient binding of II in the MMP-1 complex system has been achieved through classical molecular dynamics and molecular docking calculations. An ADMET analysis was also carried out to explore the potential future drug candidacy of II.

Identification and Benchmarking of Myokinasib-II as a Selective and Potent Chemical Probe for Exploring MLCK1 Inhibition.

Deciphering the functional relevance of every protein is crucial to developing a better (patho)physiological understanding of human biology. The discovery and use of quality chemical probes propel exciting developments for developing drugs in therapeutic areas with unmet clinical needs. Myosin light-chain kinase (MLCK) serves as a possible therapeutic target in a plethora of diseases, including inflammatory diseases, cancer, etc. Recent years have seen a substantial increase in interest in exploring MLCK biology. However, there is only one widely used MLCK modulator, namely, ML-7, that too with a narrow working concentration window and high toxicity profile leading to limited insights. Herein, we report the identification of a potent and highly selective chemical probe, Myokinasib-II, from the synthesis and structure-activity relationship studies of a focused indotropane-based compound collection. Notably, it is structurally distinct from ML-7 and hence meets the need for an alternative inhibitor to study MLCK biology as per the recommended best practices. Moreover, our extensive benchmarking studies demonstrate that Myokinasib-II displays better potency, better selectivity profile, and no nonspecific interference in relevant assays as compared to other known MLCK inhibitors.