Design,synthesis and structure–activity relationship of novel diphenylamine derivatives

Diphenylamine derivatives have been reported with good fungicidal, insecticidal, acaricidal, rodenticidal and/or herbicidal activities. To find new lead compound of this kind, a series of novel diphenylamine derivatives were designed and synthesized by the approach of Intermediate Derivatization Methods. All compounds were identified by ¹H NMR and elemental analysis. Bioassays demonstrated that some compounds substituted at 2,4,6-positions or 2,4,5-positions of phenyl ring B exhibited excellent fungicidal activities. The optimal compounds P30 and P33 showed 80% and 85% control respectively against cucumber downy mildew at 12.5 mg L⁻¹, both 100% control against rice blast at 0.3 mg L⁻¹ and both 100% control against cucumber gray mold at 0.9 mg L⁻¹. The relationship between structure and fungicidal activities was discussed as well.     

Synthesis and structure–activity relationship of novel cinnamamide derivatives as antidepressant agents

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure–activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b–c and 6a–b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.     

Synthesis and structure–activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists

A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus.     

Structure–activity relationship study of phenylpyrazole derivatives as a novel class of anti-HIV agents

The structure–activity relationship of phenylpyrazole derivative 1 was investigated for the development of novel anti-HIV agents. Initial efforts revealed that the diazenyl group can be replaced by an aminomethylene group. In addition, we synthesized various derivatives by the reductive amination of benzaldehydes with 5-aminopyrazoles and carried out parallel structural optimization on the benzyl group and the pyrazole ring. This optimization led to a six-fold more potent derivative 32j than the lead compound 1, and this derivative has a 3′,4′-dichloro-(1,1′-biphenyl)-3-yl group.     

Synthesis and structure–activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R¹ attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R². The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.     

Synthesis and structure–activity relationship study of novel quinazolinone-based inhibitors of MurA

MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure–activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC₅₀ of 8 µM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1 µg/mL to 8 µg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance.     

Identification and structure–activity relationship study of carvacrol derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors

Abstract

In the present study, we identified carvacrol, a major phenolic component of oregano oil as a novel small molecule inhibitor of Mycobacterium tuberculosis (MTB) chorismate mutase (CM) enzyme with IC₅₀ of 1.06?±?0.4?µM. Virtual screening of the BITS-Pilani in-house database using the crystal structure of the MTB CM bound transition state intermediate (PDB: 2FP2) as framework identified carvacrol as a potential lead. Further various carvacrol derivatives were evaluated in vitro for their ability to inhibit MTB CM enzyme, whole cell MTB and cytotoxicity as steps toward the derivation of structure–activity relationships (SAR) and lead optimization.     

Discovery and structure–activity relationship of thienopyridine derivatives as bone anabolic agents

A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.     

Design,synthesis, and structure–activity relationship of novel CCR2 antagonists

A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.     

Quantitative structure–activity relationship study on some benzodiazepine derivatives as anti-Alzheimer agents

A QSAR study was performed in an attempt to explore the pharmacophore of some benzodiazepine derivatives as anti-Alzheimer agents for the inhibition of -secretase. The study, which used the electrotopological state atom (ETSA) index, which encodes electronic and topological information, reveals the importance of two phenyl rings—one substituted and another unsubstituted, for the inhibition of the enzyme. Fluorine substitution on the substituted phenyl ring has an important contribution to the activity. R-configurations of the aliphatic chain substituents provide the exact conformation of the molecules to enter into the binding pockets of the receptor(s).Figure General structure of benzodiazepine containing -secretase inhibitors     

Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.     

Synthesis and structure–activity relationship of thiobarbituric acid derivatives as potent inhibitors of urease

A series of thiobarbituric acid derivatives 1–27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1–27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC₅₀ values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC₅₀ = 21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC₅₀ values 21.4 ± 1.04 and 21.5 ± 0.61μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure–activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and ¹H NMR.     

Design,synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

Abstract

Because of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure–activity relationship (SAR) of various novel {2-[(2-, 3- and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5- or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings. For graphical abstract: see Supplementary Material. (www.informahealthcare.com/enz)     

Design,synthesis, and structure–activity relationship of novel and effective apixaban derivatives as FXa inhibitors containing 1,2,4-triazole/pyrrole derivatives as P2 binding element

Four series of novel and potent FXa inhibitors possessing the 1,2,4-triazole moiety and pyrrole moiety as P2 binding element and dihydroimidazole/tetrahydropyrimidine groups as P4 binding element were designed, synthesized, and evaluated for their anticoagulant activity in human and rabbit plasma in vitro. Most compounds showed moderate to excellent activity. Compounds 14a, 16, 18c, 26c, 35a, and 35b were further examined for their inhibition activity against human FXa in vitro and rat venous thrombosis in vivo. The most promising compound 14a, with an IC₅₀ (FXa) value of 0.15 μM and 99% inhibition rate, was identified for further evaluation as an FXa inhibitor.     

Design,synthesis, and quantitative structure–activity relationship of cytotoxic γ-carboline derivatives

Three series of γ-carboline derivatives were designed and synthesized. All the compounds were tested for their cytotoxic activities in vitro against five human tumor cell lines (A549, SGC, HCT116, MCF-7, K562) and one multi-drug resistant subline (K562R). Most compounds showed moderate to potent cytotoxic activities against the tested cell lines. Sulfonate 11f exhibited more potent cytotoxic activities against almost all of the tested cells in comparison with the positive control, taxol, with IC₅₀ values ranging from 0.15 to 4.5 μM. The structure–activity relationships were discussed and a statistically reliable QSAR model (r² = 0.936, q² = 0.581) was established by the CoMFA analysis performed using the cytotoxic data against K562 cell line as a template.     

Synthesis and structure–activity relationship of 16,17-modified gibberellin derivatives

Gibberellins (GAs) are a group of diterpenoid plant hormones that control plant growth and development at various stages. Biologically active GAs share the common structures of a 3β-hydroxy group, a carboxy group at C-6, and a γ-lactone between C-4 and C-10. Hydroxylation at C-2β is a major deactivation step in many plant species, and hydroxylation at C-13 has been shown to weaken the binding affinity of GAs to their receptor proteins. In rice, bioactive GA₄ has also been shown to be deactivated through 16α,17-epoxidation. Moreover, 16,17-dihydro-16α,17-dihydroxy GA₄ has been identified as an aglycon of its glucoside from rice. However, our knowledge on the biological activity of 16,17-epoxidized GAs is currently limited to 16,17-dihydro-16α,17-epoxy GA₄. Moreover, the bioactivity of 16,17-dihydro-16α,17-dihydroxy GA₄ remains unknown. Here, we synthesized 16,17-epoxidized or dihydroxylated GA derivatives and performed a structure–activity relationship study using rice seedlings. 16,17-Epoxidation of bioactive GA₁ and GA₄ reduced their activity to promote elongation of rice leaf sheaths. Moreover, 16,17-dihydroxylation significantly decreased the activities of 16,17-dihydro-16α,17-epoxy GAs. These results suggest that GAs are deactivated in a stepwise manner via 16,17-epoxidation and hydrolysis of these epoxy groups.     

Synthesis and structure–activity relationship of 4-azaheterocycle benzenesulfonamide derivatives as new microtubule-targeting agents

A series of 1-sulfonyl indolines was synthesized and evaluated for antiproliferative activity. The most potent compounds 9a and 9e showed significant cytotoxicity (IC₅₀ in the range of 0.055–0.105 and 0.039–0.112 μM, respectively) against four human cancer cell lines HCT116, PC3, HepG2 and SK-OV-3. The structure–activity relationship of this series of sulfonamides, including the influence of azaheterocycle rings, substituent at the different positions of indoline, and the cyclopropane moiety, was described.     

Design,synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC₅₀ value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.