Compounds 4d Research Articles

Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities

Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-β-carboline (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50, 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of H2O2-induced oxidative stress.

Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases.

Exploring the synthesis, molecular structure and biological activities of novel Bis-Schiff base derivatives: A combined theoretical and experimental approach

A library of six novel bis-Schiff base derivatives (2a-f) were synthesized, characterized through modern spectroscopic techniques and screened for their α-glucosidase and α-amylase inhibitory activities (in vitro). In the series, compound 2a (IC50 = 5.64 ± 2.22 µM) and 2f (IC50 = 22.78 ± 2.37 µM) were the most potent α-amylase inhibitors while the remaining four compounds showed significant to less activity. In case of α-glucosidase inhibition, four compounds 2e (IC50 = 2.83 ± 0.18 µM), 2c (IC50 = 7.03 ± 0.15 µM), 2f (IC50 = 9.99 ± 0.20 µM), and 2d (IC50 = 14.68 ± 0.21 µM) displayed excellent inhibitory activity while two compounds showed good inhibitory activity, comparing with the standard acarbose drug. The DFT assay was used to measure the FMO of the synthesized molecules, which indicated their stability, bioactivity and charge transfer. The MEP analysis revealed the distribution of electrostatic potential on the molecular surface of 2a-f, which is helpful for understanding reactivity and interactions. The AIM study showed low hydrogen bond energy and non-covalent interactions. This implies that these molecules may have weak hydrogen bonding and non-covalent interactions, which could affect their chemical behavior. The molecular docking study has provided valuable insights into the interactions between the synthesized derivatives of 2,4-dihydroxyacetophenone with α-glucosidase and α-amylase proteins. The results not only shed light on the binding affinity and key interaction sites but also offer potential avenues for the design of novel drug candidates to control postprandial glucose level in diabetic patients.

Novel tetrahydroisoquinolines as DHFR and CDK2 inhibitors: synthesis, characterization, anticancer activity and antioxidant properties

In this study, we synthesized new 5,6,7,8-tetrahydroisoquinolines and 6,7,8,9-tetrahydrothieno[2,3-c]isoquinolines based on 4-(N,N-dimethylamino)phenyl moiety as expected anticancer and/or antioxidant agents. The structure of all synthesized compounds were confirmed by spectral date (FT-IR, 1H NMR, 13C NMR) and elemental analysis. We evaluated the anticancer activity of these compounds toward two cell lines: A459 cell line (lung cancer cells) and MCF7 cell line (breast cancer cells). All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC50: 0.155 µM) while compound 8d showed the most potent one against MCF7 cell line (IC50: 0.170 µM) in comparison with doxorubicin. In addition, we examined the effect of compounds 7e and 8d regarding the growth of A549 and MCF7 cell lines, employing flow cytometry and Annexin V-FITC apoptotic assay. Our results showed that compound 7e caused cell cycle arrest at the G2/M phase with a 79-fold increase in apoptosis of A459 cell line. Moreover, compound 8d caused cell cycle arrest at the S phase with a 69-fold increase in apoptosis of MCF7 cell line. Furthermore, we studied the activity of these compounds as enzyme inhibitors against several enzymes. Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 µM, compared to the Roscovitine control drug with IC50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 µM, compared to Methotrexate control drug with IC50 of 0.131 µM. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1, 3, 6, 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs.Graphical

Identification of 3-aryl-5-methyl-isoxazole-4-carboxamide derivatives and analogs as novel HIF-2α agonists through docking-based virtual screening and structural modification

Hypoxia-inducible factor-2 (HIF-2) serves as the pivotal transcription factor in cellular responses to low oxygen levels, particularly concerning the regulation of erythropoietin (EPO) production. A docking-based virtual screening on crystal structures of HIF-2α inhibitors unexpectedly identified 3-phenyl-5-methyl-isoxazole-4-carboxamide derivative v19 as a hit of HIF-2α agonist. Further structural optimizations of compound v19 led to the discovery of a series of HIF-2α agonists with novel scaffolds. The most promising compounds 12g and 14d exhibited potent HIF-2α agonistic activities in vitro with EC50 values of 2.29 μM and 1.78 μM, respectively. Molecular dynamics simulations have revealed their capacity to allosterically enhance HIF-2 dimerization, which shed light on their mechanism of action. Moreover, compound 14d demonstrated a favorable pharmacokinetic (PK) profile, boasting an impressive oral bioavailability value of 68.71 %. These findings strongly suggest that compound 14d is an auspicious lead compound for the treatment of renal anemia.

Design, in silico studies, synthesis, and in vitro anticancer assessment of new naphthylidene isoxazolidinedione derivatives

AbstractCancer is the most destructive and fatal disease, representing an urgent medical challenge to the world. The discovery of a new anticancer candidate may help reduce or eliminate this alarming disease to a greater extent. On similar lines, in silico research was carried out on novel naphthylidene isoxazolidinedione derivatives that were logically conceived, synthesized, purified, and structurally characterized. In vitro biological evaluation revealed the most active compound 4d with an inhibitory concentration of 42.87 µm against K562 and 47.42 µm on A549 cells. The anticancer activity of this naphthylidene isoxazolidinedione derivative was evident by cell cycle and apoptosis assays, which showed arrest of the G2/M phase (65.6%) of the K562 cells and induction of apoptosis with 21.47% apoptotic cells as compared to 0.2% of untreated cells, respectively.

Design, Synthesis, Antifungal Evaluation, Structure-Activity Relationship (SAR) Study, and Molecular Docking of Novel Spirotryprostatin A Derivatives.

Phytopathogenic fungi cause plant diseases and economic losses in agriculture. To efficiently control plant pathogen infections, a total of 19 spirotryprostatin A derivatives and 26 spirooxindole derivatives were designed, synthesized, and tested for their antifungal activity against ten plant pathogens. Additionally, the intermediates of spirooxindole derivatives were investigated, including proposing a mechanism for diastereoselectivity and performing amplification experiments. The bioassay results demonstrated that spirotryprostatin A derivatives possess good and broad-spectrum antifungal activities. Compound 4d exhibited excellent antifungal activity in vitro, equal to or higher than the positive control ketoconazole, against Helminthosporium maydis, Trichothecium roseum, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium graminearum, Alternaria brassicae, Alternaria alternate, and Fusarium solan (MICs: 8-32 µg/mL). Compound 4k also displayed remarkable antifungal activity against eight other phytopathogenic fungi, including Fusarium oxysporium f. sp. niveum and Mycosphaerella melonis (MICs: 8-32 µg/mL). The preliminary structure-activity relationships (SARs) were further discussed. Moreover, molecular docking studies revealed that spirotryprostatin A derivatives anchored in the binding site of succinate dehydrogenase (SDH). Therefore, these compounds showed potential as natural compound-based chiral fungicides and hold promise as candidates for further enhancements in terms of structure and properties.

Synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-1,2,3-triazoles as potent EGFR targeting anti-breast cancer agents

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. A general strategy was developed for the synthesis of new 1,2,3-triazoles (7a-7l & 8a-8g) containing fused [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine from 3-ethynyl-6-(4-nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 8,8-dioxide (6) and several azides using Cu(I)-catalyzed [3+2] cycloaddition method. The cancer activity of the synthesized compounds was then tested in vitro against two breast cancer cell lines, MCF-7 and MDA-MB-231, and the majority of the examined compounds 7h, 7i, 8d, and 8e showed significant activity, with compounds 7h and 8d surpassing the standard drug against two cancer cell lines, and 7i and 8e equipotent activity against tested cell lines. Later, in vitro, EGFR results revealed that compounds 7i (IC50 = 0.38 ± 0.02 μM) and 8d (IC50 = 0.41 ± 0.05 μM) were more effective than the conventional medicine Erlotinib (IC50 = 0.42 ± 0.02 μM). Finally, in silico molecular docking studies and ADMET predictions were performed for six potent compounds using the Discovery Studio 2021 protocol to support the wet lab results and drug-likeness of the compounds.

Novel oxadiazole functionalized pyridopyrimidine derivatives; their anticancer activity and molecular docking studies

AbstractA series of novel oxadiazole functionalized pyridopyrimidine derivatives prepared starting from 6‐methyl/ethyl‐2‐oxo‐4‐(trifluoromethyl)‐1,2‐dihydropyridine‐3‐carbonitrile 1. This compound 1 on reaction with sulfuric acid obtained compound 2, further compound 2 on reaction with chloroacetamide followed by reaction with ethoxy methylene malonic diethyl ester coupling and further cyclization to obtain compound 5. Compound 5 on reaction with hydrazide hydrate obtained hydrazide derivatives 6. Compound 6 on reaction with diverse substituted aromatic acids to get oxadiazole derivatives 7a–l. All the final compounds 7a–l evaluated for anticancer activity against four human cancer cell lines such as HeLa—cervical cancer (CCL‐2); COLO 205—colon cancer (CCL‐222); HepG2—liver cancer (HB‐8065); and MCF7—breast cancer (HTB‐22) and promising compounds 7d and 7k have been identified and evaluated for molecular docking interactions.

The Effect of 4-(Dimethylamino)phenyl-5-oxopyrrolidines on Breast and Pancreatic Cancer Cell Colony Formation, Migration, and Growth of Tumor Spheroids.

A series of hydrazones, azoles, and azines bearing a 4-dimethylaminophenyl-5-oxopyrrolidine scaffold was synthesized. Their cytotoxic effect against human pancreatic carcinoma Panc-1 and triple-negative breast cancer MDA-MB-231 cell lines was established by MTT assay. Pyrrolidinone derivatives 3c and 3d, with incorporated 5-chloro and 5-methylbenzimidazole fragments; hydrazone 5k bearing a 5-nitrothien-2-yl substitution; and hydrazone 5l with a naphth-1-yl fragment in the structure significantly decreased the viability of both cancer cell lines. Compounds 3c and 5k showed the highest selectivity, especially against the MDA-MB-231 cancer cell line. The EC50 values of the most active compound 5k against the MDA-MB231 cell line was 7.3 ± 0.4 μM, which were slightly higher against the Panc-1 cell line (10.2 ± 2.6 μM). Four selected pyrrolidone derivatives showed relatively high activity in a clonogenic assay. Compound 5k was the most active in both cell cultures, and it completely disturbed MDA-MB-231 cell colony growth at 1 and 2 μM and showed a strong effect on Panc-1 cell colony formation, especially at 2 μM. The compounds did not show an inhibitory effect on cell line migration by the 'wound-healing' assay. Compound 3d most efficiently inhibited the growth of Panc-1 spheroids and reduced cell viability in MDA-MB-231 spheroids. Considering these different activities in biological assays, the selected pyrrolidinone derivatives could be further tested to better understand the structure-activity relationship and their mechanism of action.

Discovery of water-soluble semicarbazide-containing sulfonamide derivatives possessing favorable anti-glaucoma effect in vivo and drug-like properties

In order to obtain topical and non-irritating anti-glaucoma drugs, novel semicarbazide-containing sulfonamide derivatives were designed and synthetized by sugar tail method in this study. The hydrophilic monosaccharides were expected to form interaction with the hydrophilic site of hCA II meanwhile the linker semicarbazides are used to further enhance water solubility, and more importantly, regulate the pH values of the target compounds in aqueous solution. First, all target compounds were synthesized and evaluated for their CA inhibitory activities. The results showed our target compounds demonstrated comparable activity to the positive control drug acetazolamide. The best derivative 11d exhibits an IC50 value of 14 nM for hCA II and 2086-fold selectivity over CA I. Subsequently, physicochemical properties study showed that the target compounds displayed very good water solubility (up to 3 %) and neutral pH value in solutions. Meanwhile, the artificial membrane permeability assay was performed to verify that the target compound could also pass through the membrane structure despite their strong water solubility. In the glaucomatous rabbit eye model, the applied topically representative compounds showed strongly lowered intraocular pressure (IOP), as 1 % or 2 % water solutions. Subsequent drug-like evaluation showed our target compounds possessed low hemolysis effect and low cytotoxicity toward human corneal epithelial cell line. Also, it was not found that these target compounds had significant inhibition of hERG and CYP. In addition, these novel analogs also displayed good liver microsomal metabolic stability and plasma stability. Finally, docking studies provided the rational binding modes of representative compounds in complex with hCA II. Taken together, these results suggested that compound 11d may be a promising hCA II inhibitor deserving further development.

BMIM]BF4 Mediated Multi-component Synthesis of Phenyl-4-(1Hpyrazol- 5-yl)-1H-pyrazolo[3,4-b]quinolin-5(4H)-ones and Evaluation of their Anti-cancer Activity

Abstract: Pyrazolo bridged quinolones scaffolds are an important building block in many of the medicinally active new chemical entities. In the current work, synthesis of phenyl-4-(1H-pyrazol-5-yl) conjugated with 1H-pyrazolo[3,4-b]quinolin-5(4H)-ones derivatives has been achieved by one-pot threecomponent reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine 1, 5,5-dimethylcyclohexane-1,3-diones 2, and 1H-pyrazole-5-carbaldehydes 3 using [BMIM]BF4 as green reaction medium with good yields. Furthermore, the synthesized compounds were evaluated for cytotoxic potential towards HeLa and DU145 cells. Of the eight derivatives, compound 4d exhibited good cytotoxicity with an IC50 value of 8.5 and 8.9 μM against DU145 and HeLa cells, respectively. The molecular docking studies revealed that compound 4d displayed good binding energy (-8.4 kcal/mol) against human checkpoint kinase 1.

Design, synthesis, in-vitro biological profiling and molecular docking of some novel oxazolones and imidazolones exhibiting good inhibitory potential against acetylcholine esterase

Heterocyclic compounds with oxazole and imidazole rings in their structure have disclosed momentous biological aptitudes. Taking into account their superlative attributes, the present study was designed to introduce a new synthetic scheme to make new derivatives with tremendous futuristic pharmacological potentialities. Series of Oxazolones were synthesized by using substituted benzaldehyde with benzyl halides to produce respective benzaldehyde derivatives 1 (a–d) which further reacted with hippuric acid to yield oxazolones 2 (a–e). Newly synthesized oxazolones then reacted with 4-chloroaniline to yield corresponding imidazolones 3 (a–e). All the compounds were characterized by using FTIR and NMR spectroscopic techniques. Docking studies of Compounds were conducted using AutoDock Vina and analyzed with PYMOL. All synthesized oxazolone and imidazolone derivatives exhibited antioxidant potential, demonstrated by their IC50 values compared to ascorbic acid standard. Oxazolone derivatives (2a–2e) exhibited good acetyl cholinesterase inhibitory potential whereas Imidazolone series did not show significant inhibition as shown by their IC50 values compared to donepezil as a standard. Docking studies of all compounds against acetylcholinesterase demonstrated favorable binding affinity, indicating their potential for further in-vivo studies. It is notable that novel compounds of both oxazolones and Imidazolone series exhibited antioxidant potential with maximum percentage inhibition of 75.9 (IC50 12.9 ± 0.0573 µM/mL) by compound 2d while compound 2a showed AChE inhibitory potential with maximum %age inhibition of 75.49 (IC50 7.8 ± 0.0218 µM/mL). Communicated by Ramaswamy H. Sarma

Exploring new imines as anti-inflammatory COX and 5-LOX inhibitors with an improved pharmacokinetic profile.

Background: Dual COX/5-LOX inhibition is a bright strategy for developing new potent and safe anti-inflammatory agents. Methods: New imines were synthesized and evaluated for their anti-inflammatory activity. The most active compounds were further investigated for their safety profile. Their molecular docking and physicochemical parameters were assessed. A new LC-MS/MS method was developed for the quantification of compound 4d in rat plasma. Results: Synthesized compounds were found to have anti-inflammatory activity (77-88% edema inhibition). In addition, 4d, 5m and 7d showed analgesic activity (92.50, 95.71and 96.28% protection, respectively). 4d showed dual COX-2/5-LOX activity. Molecular docking expected the binding pattern of compounds in COX-1, COX-2and 5-LOX active sites. The in vivo pharmacokinetic parameters of compound 4d were also obtained.

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof

New thymol–3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC50= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC50= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a–l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a–f, 6i–l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h–l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

Investigations of new N1-substituted pyrazoles as anti-inflammatory and analgesic agents having COX inhibitory activity.

Background: The search is ongoing forideal anti-inflammatory and analgesic agents with promising potency and reasonable selectivity. Methods: New N1-substituted pyrazoles with or without anacetamide linkage were synthesized and evaluated for their anti-inflammatory and analgesic activities. COX inhibitory testing, molecular docking, molecular dynamics simulation and antiproliferative activity assessmentswere performed. Results: All compounds exhibited anti-inflammatory activity up to 90.40% inhibition. They also exhibitedgood analgesic activity with up to 100% protection. N1-benzensulfonamides 3d, 6c and 6h were preferentially selective agents towardCOX-2. Compound 3d showed good cytotoxicity against MCF-7 and HTC116 cancer cell lines. Molecular modeling studies predicted the binding pattern of the most active compounds. Molecular dynamics confirmed the docking results. All compounds showedremarkable pharmacokinetic properties.

New pyranopyrazole based derivatives: Design, synthesis, and biological evaluation as potential topoisomerase II inhibitors, apoptotic inducers, and antiproliferative agents

A new series of pyranopyrazole-based derivatives were designed and synthesized. The synthesized compounds were assessed for their cytotoxic efficacy against A549 human lung carcinoma and MCF-7 human breast carcinoma cell lines. Three compounds (1b, 4b, and 7b) exhibited 1.3- to 2.3-fold more antiproliferative activity than that of doxorubicin against the A549 cell line. In comparison to doxorubicin, compounds 1d and 3b were 4.1- and 1.04-fold, respectively more powerful against MCF-7 cancer cells. All the synthesized compounds were found to be more selective toward A549 cancer cells than the normal human fibroblast BJ cells. Of interest, compounds 1b and 7b exhibited promising cytotoxicity and SIs of 27.72 and 25.30, respectively, towards A549 cancer cells, higher than that of doxorubicin (SI 4.81). The most potent compounds 1b, 1d, 3b, 4b, and 7b were then subjected to in vitro Topo II inhibition assay. They showed IC50 values in the range of 2.07 to 8.86 µM. Of particular interest, compound 7b (IC50 = 2.07 µM), exhibited higher Topo II inhibitory activity than that of doxorubicin (IC50 = 2.56 µM). The significant Topo II inhibition of compound 7b was explained by molecular docking simulations into the Topo II active site. Compound 7b halted the cell cycle in the S phase in A549 cancer cells. It induced total apoptosis and necrosis of 20.73- and 4-fold, respectively, greater than the control. This evidence was supported by a 3.59-fold increase in the level of apoptotic caspase-9 and a remarkable elevation of the Bax/BCL-2 ratio. The physiochemical parameters of compound 7b were aligned with Lipinski’s rule of five.

Multifaceted bioactivity of thiosemicarbazide derivatives: Synthesis, characterization, and DFT investigations on inhibition of α-amylase, hydroxyl radical scavenging, and iron chelating activities with molecular docking insights

In this study, eight bioactive thiosemicarbazide derivatives (3a-h) were synthesized and characterized through 1HNMR , 13CNMR and Mass spectroscopic techniques. Finally, their inhibition activities against α-amylase and antioxidant activity were investigated. Among the synthetic series, five compounds 3 g (IC50 = 8.61 ± 1.42 µM) 3a (IC50 = 13.41 ± 1.65 µM), 3e (IC50 = 15.23 ± 1.17 µM), 3 h (IC50 = 17.37 ± 0.87 µM) and 3d (IC50 = 17.95 ± 1.99 µM) showed excellent inhibition by comparing with standard (acarbose, IC50 = 21.55 ± 1.31 µM). Similarly, in the case of iron chelating agent activity, product compounds 3a-h presented outstanding activity in the range of IC50 = 18.19 ± 1.81 to 63.42 ± 1.45 µM superior than standard (EDTA, IC50 = 66.43 ± 1.07 µM) while in hydroxyl radical scavenging activity all the synthesized products 3a-h also showed excellent scavenging activity in the range of IC50 values 25.85 ± 1.13 to 58.9 ± 2.95 µM when compared to standard vitamin C (IC50 = 60.51 ± 1.02 µM). We expanded our investigation to molecular interactions via a docking study, where these compounds were docked with the target protein to unveil their binding affinities and key interactions, offering additional insights into their inhibitory mechanisms. The chemical nature of the synthesized compounds was revealed through density functional theory (DFT) calculations at B3LYP/6–311++G(d,p). Intramolecular hydrogen bonding was explored using DFT-d3 and reduced density gradient (RDG) analysis. Additionally, various reactivity parameters were investigated through TD-DFT at the CAM-B3LYP/6–311++G(d,p) method.

Scaffold hopping for designing of potent and selective CYP1B1 inhibitors to overcome docetaxel resistance: synthesis and evaluation

Cytochrome P450 1B1, a tumor-specific overexpressed enzyme, significantly impairs the pharmacokinetics of several commonly used anticancer drugs including docetaxel, paclitaxel and cisplatin, leading to the problem of resistance to these drugs. Currently, there is no CYP1B1 inhibition-based adjuvant therapy available to treat this resistance problem. Hence, in the current study, exhaustive in-silico studies including scaffold hopping followed by molecular docking, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular dynamics and free energy perturbation studies were carried out to identify potent and selective CYP1B1 inhibitors. Initially, scaffold hopping analysis was performed against a well-reported potent and selective CYP1B1 inhibitor (i.e. compound 3n). A total of 200 scaffolds were identified along with their shape and field similarity scores. The top three scaffolds were further selected on the basis of these scores and their synthesis feasibility to design some potent and selective CYP1B1 inhibitors using the aforementioned in-silico techniques. Designed molecules were further synthesized to evaluate their CYP1B1 inhibitory activity and docetaxel resistance reversal potential against CYP1B1 overexpressed drug resistance MCF-7 cell line. In-vitro results indicated that compounds 2a, 2c and 2d manifested IC50 values for CYP1B1 ranging from 0.075, 0.092 to 0.088 μM with at least 10-fold selectivity. At low micromolar concentrations, compounds 1e, 1f, 2a and 2d exhibited promising cytotoxic effects in the docetaxel-resistant CYP1B1 overexpressed MCF-7 cell line. In particular, compound 2a is most effective in reversing the resistance with IC50 of 29.0 ± 3.6 μM. All of these discoveries could pave the way for the development of adjuvant therapy capable of overcoming CYP1B1-mediated resistance. Communicated by Ramaswamy H. Sarma

Design, Synthesis, and Herbicidal Activity of Substituted 3-(Pyridin-2-yl)Phenylamino Derivatives.

To discover protoporphyrinogen oxidase (PPO) inhibitors with robust herbicidal activity and crop safety, three types of substituted 3-(pyridin-2-yl)phenylamino derivatives bearing amide, urea, or thiourea as side chain were designed via structure splicing strategy. Postemergence herbicidal activity assessment of 33 newly prepared compounds revealed that many of our compounds such as 6a, 7b, and 8d exhibited superior herbicidal activities against broadleaf and monocotyledon weeds to commercial acifluorfen. In particular, compound 8d exhibited excellent herbicidal activities and high crop safety at a dosage range of 37.5-150 g ai/ha. PPO inhibitory studies supported our compounds as typical PPO inhibitors. Molecular docking studies revealed that compound 8d provided effective interactions with Nicotiana tabacum PPO (NtPPO) via diverse interaction models, such as π-π stacking and hydrogen bonds. Molecular dynamics (MD) simulation studies and degradation studies were also conducted to gain insight into the inhibitory mechanism. Our study indicates that compound 8d may be a candidate molecule for the development of novel herbicides.