ABSTRACT
4-Fluoro-N-(thiazol-2-yl)benzenesulfonamide (3) is a novel fluorinated compound, containing various biological activities. Therefore, absorption spectroscopy, fluorescence quenching, molecular docking, and molecular simulation were employed to investigate the interaction between 3 and HSA. Firstly, compound 3 meets all criteria for drug-likeness prediction. UV absorption spectra revealed the interaction of 3 with HSA altered the microenvironment of protein, as well as circular dichroism spectroscopic analysis indicated slightly conformational changes and a reduction in α-helical content. The binding parameters of the HSA-3 complex suggested that fluorescence quenching is driven by combined static and dynamic processes. Additionally, the stability of the complex is attributed to conventional hydrogen and hydrophobic bonding interactions. Furthermore, esterase-like activity indicated that the binding of 3 might disrupt HSA's bond networks, leading to structural alterations. Consequently, the strong binding constant (Kaâ¯≈â¯1.204â¯×â¯106â¯M-1) aligns with the predicted unbound fraction (0.28) in serum, indicating that thiazole 3 has good bioavailability in plasma and can be effectively transported to target sites, thereby exerting its pharmaceutical effects. However, careful dosage management is essential to prevent potential adverse effects. Overall, these findings highlight the potential of 3 as a therapeutic agent, emphasizing the need for further research to optimize its uses.
ABSTRACT
Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.
Subject(s)
Agaricales , Dose-Response Relationship, Drug , Enzyme Inhibitors , Monophenol Monooxygenase , Naphthoquinones , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Naphthoquinones/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Agaricales/enzymology , Structure-Activity Relationship , Molecular Structure , Molecular Docking Simulation , Molecular Dynamics SimulationABSTRACT
The discovery of novel bioactive molecules as potential multifunctional neuroprotective agents has clinically drawn continual interest due to devastating oxidative damage in the pathogenesis and progression of neurodegenerative diseases. Synthetic 8-aminoquinoline antimalarial drug is an attractive pharmacophore in drug development and chemical modification owing to its wide range of biological activities, yet the underlying molecular mechanisms are not fully elucidated in preclinical models for oxidative damage. Herein, the neuroprotective effects of two 8-aminoquinoline-uracil copper complexes were investigated on the hydrogen peroxide-induced human neuroblastoma SH-SY5Y cells. Both metal complexes markedly restored cell survival, alleviated apoptotic cascades, maintained antioxidant defense, and prevented mitochondrial function by upregulating the sirtuin 1 (SIRT1)/3-FOXO3a signaling pathway. Intriguingly, in silico molecular docking and pharmacokinetic prediction suggested that these synthetic compounds acted as SIRT1 activators with potential drug-like properties, wherein the uracil ligands (5-iodoracil and 5-nitrouracil) were essential for effective binding interactions with the target protein SIRT1. Taken together, the synthetic 8-aminoquinoline-based metal complexes are promising brain-targeting drugs for attenuating neurodegenerative diseases.
ABSTRACT
This work presents a flexible synthesis of 10 novel naphthoquinone-chalcone derivatives (1-10) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC50 values in the range of 0.81-62.06 µM, especially the four most potent compounds 1, 3, 8, and 9. The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives (1-2, 4-5, and 7-10) were active FGFR1 inhibitors (IC50 = 0.33-3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC50 = 12.17 nM). Promisingly, compounds 5 (IC50 = 0.33 ± 0.01 nM), 9 (IC50 = 0.50 ± 0.04 nM), and 7 (IC50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5, 7, and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone-chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.
ABSTRACT
Encouraged by the lack of effective treatments and the dramatic growth in the global prevalence of neurodegenerative diseases along with various pharmacological properties of chalcone pharmacophores, this study focused on the development of aminochalcone-based compounds, organic molecules characterized by a chalcone backbone (consisting of two aromatic rings connected by a three-carbon α,ß-unsaturated carbonyl system) with an amino group attached to one of the aromatic rings, as potential neuroprotective agents. Thus, the aminochalcone-based compounds in this study were designed by bearing a -OCH3 moiety at different positions on the ring and synthesized by the Claisen-Schmidt condensation. The compounds exhibited strong neuroprotective effects against hydrogen peroxide-induced neuronal death in the human neuroblastoma (SH-SY5Y) cell line (i.e., by improving cell survival, reducing reactive oxygen species production, maintaining mitochondrial function, and preventing cell membrane damage). The aminochalcone-based compounds showed mild toxicity toward a normal embryonic lung cell line (MRC-5) and a human neuroblastoma cell line, and were predicted to have preferable pharmacokinetic profiles with potential for oral administration. Molecular docking simulation indicated that the studied aminochalcones may act as competitive activators of the well-known protective protein, SIRT1, and provided beneficial knowledge regarding the essential key chemical moieties and interacting amino acid residues. Collectively, this work provides a series of four promising candidate agents that could be developed for neuroprotection.
ABSTRACT
A series of sixteen acetamidosulfonamide derivatives (1-16) have been synthesized and investigated for their antioxidant (radical scavenging and superoxide dismutase (SOD)) and antimicrobial activities. Most compounds exhibited antioxidant activities in which compound 15 displayed the most potent radical scavenging and SOD activities. Quantitative structure-activity relationship (QSAR) has been studied using multiple linear regression. The constructed QSAR models displayed high correlation coefficient (Q 2 LOO-CV = 0.9708 and 0.8753 for RSA and SOD activities, respectively), but low root mean square error (RMSE LOO-CV = 0.5105 and 1.3571 for RSA and SOD activities, respectively). The structure-activity relationship showed that an ethylene group connected to pyridine ring provided significant antioxidant activities. The QSAR models give insight into the rational designed of eighty new sulfonamides with various electron donating and withdrawing groups. The top five new designed sulfonamides with nitro group are potential antioxidants to be further developed for medicinal applications.
ABSTRACT
Parkinson's disease (PD) is considered one of the health problems in the aging society. Due to the limitations of currently available drugs in preventing disease progression, the discovery of novel neuroprotective agents has been challenged. Sulfonamide and its derivatives were reported for several biological activities. Herein, a series of 17 bis-sulfonamide derivatives were initially tested for their neuroprotective potential and cytotoxicity against the 6-hydroxydopamine (6-OHDA)-induced neuronal death in SH-SY5Y cells. Subsequently, six compounds (i.e., 2, 4, 11, 14, 15, and 17) were selected for investigations on underlying mechanisms. The data demonstrated that the pretreatment of selected compounds (5 µM) can significantly restore the level of cell viability, protect against mitochondrial membrane dysfunction, decrease the activity of lactate dehydrogenase (LDH), decrease the intracellular oxidative stress, and enhance the activity of NAD-dependent deacetylase sirtuin-1 (SIRT1). Molecular docking was also performed to support that these compounds could act as SIRT1 activators. In addition, in silico pharmacokinetic and toxicity profile prediction was also conducted for guiding the potential development. Thus, the six neuroprotective bis-sulfonamides were highlighted as potential agents to be further developed for PD management.
ABSTRACT
Sulfur-containing compounds are considered as attractive pharmacophores for discovery of new drugs regarding their versatile properties to interact with various biological targets. Quantitative structure-activity relationship (QSAR) modeling is one of well-recognized in silico tools for successful drug discovery. In this work, a set of 38 sulfur-containing derivatives (Types I-VI) were evaluated for their in vitro anticancer activities against 6 cancer cell lines. In vitro findings indicated that compound 13 was the most potent cytotoxic agent toward HuCCA-1 cell line (IC50 = 14.47 µM). Compound 14 exhibited the most potent activities against 3 investigated cell lines (i.e., HepG2, A549, and MDA-MB-231: IC50 range = 1.50-16.67 µM). Compound 10 showed the best activity for MOLT-3 (IC50 = 1.20 µM) whereas compound 22 was noted for T47D (IC50 = 7.10 µM). Subsequently, six QSAR models were built using multiple linear regression (MLR) algorithm. All constructed QSAR models provided reliable predictive performance (training sets: Rtr range = 0.8301-0.9636 and RMSEtr = 0.0666-0.2680; leave-one-out cross validation sets: RCV range = 0.7628-0.9290 and RMSECV = 0.0926-0.3188). From QSAR modeling, chemical properties such as mass, polarizability, electronegativity, van der Waals volume, octanol-water partition coefficient, as well as frequency/presence of C-N, F-F, and N-N bonds in the molecule are essential key predictors for anticancer activities of the compounds. In summary, a series of promising fluoro-thiourea derivatives (10, 13, 14, 22) were suggested as potential molecules for future development as anticancer agents. Key structure-activity knowledge obtained from the QSAR modeling was suggested to be advantageous for suggesting the effective rational design of the related sulfur-containing anticancer compounds with improved bioactivities and properties.
ABSTRACT
Epidermal growth factor receptor (EGFR) has been recognized as one of the attractive targets for anticancer drug development. Herein, a set of anilino-1,4-naphthoquinone derivatives (3-18) was synthesized and investigated for their anticancer and EGFR inhibitory potentials. Among all tested compounds, three derivatives (3, 8, and 10) were selected for studying EGFR inhibitory activity (in vitro and in silico) due to their most potent cytotoxic activities against six tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, MDA-MB-231, and T47D; IC50 values = 1.75-27.91 µM), high selectivity index (>20), and good predicted drug-like properties. The experimental results showed that these three promising compounds are potent EGFR inhibitors with nanomolar IC50 values (3.96-18.64 nM). Interestingly, the most potent compound 3 bearing 4-methyl substituent on the phenyl ring displayed 4-fold higher potency than the known EGFR inhibitor, erlotinib. Molecular docking, molecular dynamics simulation, and MM/GBSA-based free energy calculation revealed that van der Waals force played a major role in the accommodations of compound 3 within the ATP-binding pocket of EGFR. Additionally, the 4-CH3 moiety of the compound was noted to be a key chemical feature contributing to the highly potent EGFR inhibitory activity via its formations of alkyl interactions with A743, K745, M766, and L788 residues as well as additional interactions with M766 and T790.
ABSTRACT
A library of 44 indole-sulfonamide derivatives (1-44) were investigated for their cytotoxic activities against four cancer cell lines (i.e., HuCCA-1, HepG2, A549, and MOLT-3) and antimalarial effect. Most of the studied indoles exhibit anticancer activity against the MOLT-3 cell line, whereas only hydroxyl-containing bisindoles displayed anticancer activities against the other tested cancer cells as well as antimalarial effect. The most promising anticancer compounds were noted to be CF3, Cl, and NO2 derivatives of hydroxyl-bearing bisindoles (30, 31, and 36), while the most promising antimalarial compound was an OCH3 derivative of non-hydroxyl-containing bisindole 11. Five quantitative structure-activity relationship (QSAR) models were successfully constructed, providing acceptable predictive performance (training set: R = 0.6186-0.9488, RMSE = 0.0938-0.2432; validation set: R = 0.4242-0.9252, RMSE = 0.1100-0.2785). QSAR modeling revealed that mass, charge, polarizability, van der Waals volume, and electronegativity are key properties governing activities of the compounds. QSAR models were further applied to guide the rational design of an additional set of 22 compounds (P1-P22) in which their activities were predicted. The prediction revealed a set of promising virtually constructed compounds (P1, P3, P9, P10, and P16) for further synthesis and development as anticancer and antimalarial agents. Molecular docking was also performed to reveal possible modes of bindings and interactions between the studied compounds and target proteins. Taken together, insightful structure-activity relationship information obtained herein would be beneficial for future screening, design, and structural optimization of the related compounds.
ABSTRACT
Lead mixed-halide perovskites are promising absorption materials that are suitable for applications in tandem solar cells using existing silicon technology. Charge-carrier mobility is an important factor that affects the performance of tandem solar cells. However, a detailed understanding of the fundamental mechanisms of lead mixed-halide perovskites remains elusive. Here, we used LO (longitudinal optical) phonons and alloy scattering to the elucidate charge-carrier mobilities in the FA0.83Cs0.17Pb(I1-xBrx)3 hybrid perovskite system. It was found that these scattering mechanisms provided very good quantitative agreement with the experimental results, between 11-40 cm2 V-1 s-1. Our findings provide new insights into charge transport scattering in lead mixed-halide hybrid perovskites and pave the way toward design of novel semiconductor alloys for solar cell applications.
ABSTRACT
5-Amino-8-hydroxyquinoline (5A8HQ), an amino derivative of 8-hydroxyquinoline, has become a potential anticancer candidate because of its promising proteasome inhibitory activity to overcome and yet synergize bortezomib for fighting cancers. Therefore, in this study, its physicochemical properties and interaction activities with serum protein have extensively been elucidated by both in vitro and in silico approaches to fulfill the pharmacokinetic and pharmacodynamic gaps. 5A8HQ exhibited the drug-likeness properties, where oral administration seems to be a route of choice owing to its high-water solubility and intestinal absorptivity. Multi-spectroscopic investigations suggested that 5A8HQ tended to associate with bovine serum albumin (BSA), a representative of serum protein, via the ground-state complexation. It apparently bound in a protein cleft between subdomains IIA and IIIA of BSA as suggested by the molecular docking and molecular dynamics simulations. The binding was mainly driven by hydrogen bonding and electrostatic interactions with a moderate binding constant at 104 M-1, conforming with the predicted free fraction in serum at 0.484. Therefore, 5A8HQ seems to display a good bioavailability in plasma to reach target sites and exerts its potent pharmacological activity. Likewise, serum albumin is a good candidate to be reservoir and transporter of 5A8HQ in the circulatory system.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Hydroxyquinolines/chemistry , Hydroxyquinolines/pharmacology , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/metabolism , Animals , Binding Sites , Cattle , Circular Dichroism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Protein Conformation , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , ThermodynamicsABSTRACT
The development of novel neuroprotective agents is urgently needed for the treatment of neurodegenerative diseases, affecting aging individuals worldwide. In this study, a new set of chalcone-triazole hybrids (6a-g) was synthesized and evaluated for their biological properties including cytotoxicity, antioxidant, anti-apoptosis, and neuroprotection using SH-SY5Y cells. The results showed that 6a and 6e provided neuroprotection in oxidative stress-induced neuronal cell damage. Both compounds significantly improved the morphology of neurons and obviously increased cell survival rate of neuronal cells induced by oxidative stress. Additionally, 6a and 6e counteracted H2O2induced mitochondrial dysfunction, which was supported by maintaining mitochondrial membrane potential, attenuating BAX protein, and increasing BCL2 protein within the mitochondria as well as upregulating SOD2 mitochondrial antioxidant enzyme. Interestingly, these compounds promoted neuroprotection via SIRT-FOXO3a signaling pathway similar to resveratrol. The data indicated that the chalcone-triazole derivatives (6a and 6e) could be considered to be promising compounds toward the discovery of disease-modifying candidates for a neurodegenerative therapy.
Subject(s)
Antioxidants/pharmacology , Chalcones/pharmacology , Neuroprotective Agents/pharmacology , Triazoles/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chalcones/chemistry , Dose-Response Relationship, Drug , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , Membrane Potential, Mitochondrial/drug effects , Molecular Structure , Neurons/drug effects , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Oxidative Stress/drug effects , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
Novel thirteen triazole-tetrahydroisoquinoline derivatives (2a-m) were synthesized and evaluated for their aromatase inhibitory activities. Seven triazoles showed significant aromatase inhibitory activity (IC50â¯=â¯0.07-1.9⯵M). Interestingly, the analog bearing naphthalenyloxymethyl substituent at position 4 of the triazole ring (2i) displayed the most potent aromatase inhibitory activity (IC50â¯=â¯70â¯nM) without significant cytotoxicity to a normal cell. Molecular docking also suggested that the direct H-bonding interaction with residue Thr310 may be responsible for a striking inhibitory effect of the most potent compound 2i.
Subject(s)
Aromatase Inhibitors/pharmacology , Tetrahydroisoquinolines/chemistry , Triazoles/chemistry , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Docking Simulation , Spectrum Analysis/methods , Structure-Activity RelationshipABSTRACT
Oxidative stress has been documented as one of the significant causes of neurodegenerative diseases. Therefore, antioxidant therapy for the prevention of neurodegenerative diseases seems to be an interesting strategy in drug discovery. The quinoline-based compound, namely 5-nitro-8-quinolinol (NQ), has shown excellent antimicrobial, anticancer, and anti-inflammatory activities. However, its neuroprotective effects and precise molecular mechanisms in human neuronal cells have not been elucidated. In this work, the effects of NQ on cell viability and morphology were evaluated by the MTT assay and microscopic observation. Moreover, the underlying mechanisms of this compound, inducing the survival rate of neuronal cells under oxidative stress, were investigated by reactive oxygen species (ROS) assay, flow cytometry, Western blotting, and immunofluorescence techniques. In addition, the molecular interaction of sirtuin1 (SIRT1) with NQ was constructed using the AutoDock 4.2 program. Interestingly, NQ protected SH-SY5Y cells against H2O2-induced neurotoxicity through scavenging ROS, upregulating the levels of SIRT1 and FOXO3a, increasing the levels of antioxidant enzymes (catalase and superoxide dismutase), promoting antiapoptotic BCL-2 protein expression, and reducing apoptosis. Besides, molecular docking also revealed that NQ interacted satisfactorily with the active site of SIRT1 similar to the resveratrol, which is the SIRT1 activator and strong antioxidant. These findings suggest that NQ prevents oxidative-stress-induced neurodegeneration because of its antioxidant capacity as well as antiapoptotic property through SIRT1-FOXO3a signaling pathway. Thus, NQ might be a drug that could be repurposed for prevention of neurodegeneration.
Subject(s)
Drug Repositioning , Neurodegenerative Diseases/prevention & control , Neurons/drug effects , Nitroquinolines/pharmacology , Protective Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Forkhead Box Protein O3/metabolism , Humans , Hydrogen Peroxide/toxicity , Molecular Docking Simulation , Neurons/metabolism , Neurons/pathology , Reactive Oxygen Species/metabolism , Sirtuin 1/metabolismABSTRACT
A library of bis-sulfonamides (9-26) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC50 range of 0.05-11.6⯵M except for compound 23. The analogs 15 and 16 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC50 values (i.e., 50 and 60â¯nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (15 and 16) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (15 and 16) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.
Subject(s)
Aromatase Inhibitors/pharmacology , Sulfonamides/pharmacology , Aromatase/chemistry , Aromatase/metabolism , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/metabolism , Binding Sites , Cell Line, Tumor , Humans , Molecular Docking Simulation , Molecular Structure , Protein Binding , Quantitative Structure-Activity Relationship , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
A three series of thioureas, monothiourea type I (4a-g), 1,4-bisthiourea type II (5a-h) and 1,3-bisthiourea type III (6a-h) were synthesized. Their aromatase inhibitory activities have been evaluated. Interestingly, eight thiourea derivatives (4e, 5f-h, 6d, 6f-h) exhibited the aromatase inhibitory activities with IC50 range of 0.6-10.2⯵M. The meta-bisthiourea bearing 4-NO2 group (6f) and 3,5-diCF3 groups (6h) were shown to be the most potent compounds with sub-micromolar IC50 values of 0.8 and 0.6⯵M, respectively. Molecular docking also revealed that one of the thiourea moieties of these two compounds could mimic steroidal backbone of the natural androstenedione (ASD) via hydrophobic interactions with enzyme residues (Val370, Leu477, Thr310, and Phe221 for 6f, Val370, Leu477, Ser478, and Ile133 for 6h). This is the first time that the bisthioureas have been reported for their potential to be developed as aromatase inhibitors, in which the 4-NO2 and 3,5-diCF3 analogs have been highlighted as promising candidates.
Subject(s)
Aromatase Inhibitors/pharmacology , Thiourea/analogs & derivatives , Thiourea/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aromatase/chemistry , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Binding Sites , Humans , Hydrophobic and Hydrophilic Interactions , MCF-7 Cells , Molecular Docking Simulation , Molecular Structure , Thiourea/chemical synthesisABSTRACT
Thirty four of indoles bearing sulfonamides (11-44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7-15.3 µM. Indoles (27-36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 µM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds. The most potent analog 28 could mimic H-bond interactions of the natural androstenedione with MET374 and ASP309 residues on the aromatase. QSAR model also revealed that the para-phenoxy indole (28) affords the higher value of electronegativity descriptor MATS6e as well as the higher inhibitory activity compared with that of the ortho-phenoxy compound (34). The study highlighted a series of promising indoles to be potentially developed as novel aromatase inhibitors for therapeutics.
Subject(s)
Aromatase Inhibitors/pharmacology , Aromatase/metabolism , Indoles/pharmacology , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Sulfonamides/pharmacology , Animals , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Multivariate Analysis , Sulfonamides/chemistry , Vero CellsABSTRACT
A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors.
ABSTRACT
BACKGROUND: Cancer has been considered to be a global health concern due to the impact of disease on the quality of life. The continual increase of cancer cases as well as the resistance of cancer cells to the existing drugs have driven the search for novel anticancer drugs with better potency and selectivity, improved pharmacokinetic profiles, and minimum toxicities. Pyridine and pyrimidine are presented in natural products and genetic materials. These pyridine/pyrimidine core structures have been noted for their roles in many biological processes as well as in cancer pathogenesis, which make such compounds become attractive scaffolds for discovery of novel drugs. RESULTS & CONCLUSION: In the recent years, pyridine- and pyrimidine-based anticancer drugs have been developed based on structural modification of these core structures (i.e., substitution with moieties and rings, conjugation with other compounds, and coordination with metal ions). Detailed discussion is provided in this review to highlight the potential of these small molecules as privileged scaffolds with attractive properties and biological activities for the search of novel anticancer agents.