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,biological activity and structure–activity relationship of endomorphin-1/substance P derivatives

Endomorphins have been shown to produce potent analgesia in various rodent models of pain. However, their central administration led to the development of tolerance and physical dependence. Conjugation of C-terminal substance P (SP) fragments to opioids and opioid peptides was previously shown to produce hybrid peptides with strong analgesic activity, with low or no propensity to develop tolerance. In this study, four peptides (2–5) comprised of endomorphin-1 (1) and C-terminal fragments of SP (four or five amino acids, SP_8–11 (2) or SP_7–11 (4), respectively), with an overlapping Phe residue, were synthesized. To overcome low metabolic stability and poor membrane permeability of the peptide, the N-terminus of 2 and 4 was further modified with a C10-carbon lipoamino acid (C10LAA) achieving 3 and 5, respectively. LAA-modification of the hybrid peptides resulted in a significant increase in metabolic stability and membrane permeability compared to peptides 1, 2 and 4. Compound 5 showed potent μ-opioid receptor binding affinity (K_iμ = 3.87 ± 0.51 nM) with dose-dependent agonist activity in the nanomolar range (IC₅₀ = 45 ± 13 nM). In silico modeling was used to investigate the binding modes and affinities of compounds 1–5 in the active site of μ-opioid receptors. The docking scores were in agreement with the K_iμ values obtained in the receptor binding affinity studies. The more active LAA-modified hybrid peptide showed a lower total interaction energy and higher negative value of MolDock score.     

Synthesis,antibiotic activity and structure–activity relationship study of some 3-enaminetetramic acids

The synthesis and evaluation of 3-enaminetetramic acids as antibacterial agents is reported; contrary to the analogous 3-acyltetramic acids, the enaminetetramic acid class of compound exhibits modest antibacterial activity against a limited spectrum of organisms, and even that activity is strongly dependent on the identity of the tetramate ring substituents. Moreover, these compounds appear to have a different mode of action to the analogous 3-acyltetramic acids, and appear to offer more limited opportunity for further elaboration in drug discovery.     

Synthesis,evaluation and quantitative structure–activity relationship (QSAR) analysis of Wogonin derivatives as cytotoxic agents

A novel series of 49 wogonin derivatives were synthesized by introducing group at 7-, 8- or B ring of wogonin. The cytotoxic activities against HepG2, A549 and BCG-823 cancer cell lines were also investigated in vitro. Several of them showed obvious cytotoxic activities and compound 3h possessed the highest potency against HepG2, A549, and BCG-823 with IC₅₀ values of 1.07 μM, 1.74 μM and 0.98 μM, respectively. A quantitative structure-activity relationship (QSAR) study of these synthetic derivatives as well as wogonin indicated that high solubility and low octanol/water partition coefficient are favorable, and excessive electrostatic properties and refractivity are unfavorable for the cytotoxic activities of these wogonin derivatives. These findings and results provide a base for further investigations.     

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 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.     

Synthesis and structure–activity relationship of 2-phenyliminochromene derivatives as inhibitors for aldo–keto reductase (AKR) 1B10

Inhibitors of a human member (AKR1B10) of the aldo–keto reductase superfamily are regarded as promising therapeutics for the treatment of cancer. Recently, we have discovered (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) as the potent competitive inhibitor using the virtual screening approach, and proposed its 4-methoxy group on the 2-phenylimino moiety as an essential structural prerequisite for the inhibition. In this study, 18 derivatives of 1 were synthesized and their inhibitory potency against AKR1B10 evaluated. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (5n) was the most potent inhibitor showing a K_i value of 1.3 nM. The structure–activity relationship of the derivatives indicated that the 7-hydroxyl group on the chromene ring, but not the 4-methoxy group, was absolutely required for inhibitory activity, The molecular docking of 5n in AKR1B10 and site-directed mutagenesis of the enzyme residues suggested that the hydrogen-bond interactions between the 7-hydroxyl group of 5n and the catalytic residues (Tyr49 and His111) of the enzyme, together with a π-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition.     

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.     

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 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.     

Synthesis,antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a–3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a–4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a–3f and 1,1′-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.     

Synthesis,central nervous system activity and structure–activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization

Abstract

A series of 20?N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization was designed as compounds having double antinociceptive and serotoninergic activity. Ethyl {[(1-arylimidazolidin-2-ylidene)carbamoyl]amino}acetates were prepared from 1-aryl-4,5-dihydro-1H-imidazol-2-amines and ethyl isocyanatoacetate, and then converted with ammonia solution to 2-{[(1-phenylimidazolidin-2-ylidene)carbamoyl]amino}acetamides. Both series of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneureas were subjected to cyclization to respective imidazo[1,2-a][1,3,5]triazines. Chain and cyclic compounds bearing ester moiety affected spontaneous locomotor activity, body temperature of mice as well as showed antinociceptive and serotoninergic activity. Interestingly, their antinociceptive activity was not reversed by naloxone, thus it is not mediated through the opioid system. Chain and cyclic compounds bearing amide moiety were devoid of central nervous system (CNS) activity which may be attributed to unfavorably low lipophilicity (connected with too high polar surface area and too small molecular volume) and poor blood–brain barrier permeation properties.     

Synthesis and antitumor activity of β-carboline 3-(substituted-carbohydrazide) derivatives

A series of β-carboline derivatives bearing a substituted-carbohydrazide moiety at C-3 were synthesized and evaluated for their antitumor activity against eight human cancer cell lines. The β-carboline N-(substituted-benzylidene)carbohydrazides showed, in general, a greater antitumor activity than their N-(alkylidene)carbohydrazide analogues. The N(9)-methylation of β-carboline N-(substituted-benzylidene) carbohydrazides resulted in a decrease of antitumor activity. Among compounds tested, the benzylidene-carbohydrazides 3, 4, 11, 13, 16, 21 and 22 were the most active, possessing IC(50) less than 10 μM for six of the eight tumor cell lines assayed. The derivative 4 displayed the most significant activity toward all tested cell lines, with a remarkable cytotoxicity against renal (786-0) cell lines (IC(50)=0.04 μM). Compound 4 was assayed for its in vivo antineoplastic activity in the Ehrlich solid carcinoma assay.     

Synthesis and structure–activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor

4-((1H-Imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed moderate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3 receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific binding to the human histamine H3 receptor.     

Synthesis and structure–activity relationship of p-carborane-based non-secosteroidal vitamin D analogs

1α,25-Dihydroxyvitamin D₃ [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure–activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure–activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.     

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.     

Synthesis,structure and anti-acetylcholinesterase activity of 4β-methoxymethyl-4β-demethyl territrem B

4β-Methoxymethyl-4β-demethyl territrem B [5] was synthesized from 4β-hydroxymethyl-β-demethyl territrem B [4] by treatment with dimethyl sulfate in methanolic NaOH. The structure of 5 was elucidated by uv, nmr and mass spectra. The IC50 of 5 on acetylcholinesterase (AChE) was 6.30 × 10-5 M, which indicated 0.4% of the anti-AChE activity of territrem B [2]. This revised version was published online in August 2006 with corrections to the Cover Date.     

Synthesis,structure–activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors

The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson’s reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.     

2-Thienyl-4-furyl-6-aryl pyridine derivatives: Synthesis,topoisomerase I and II inhibitory activity,cytotoxicity, and structure–activity relationship study

Designed and synthesized 60 2-thienyl-4-furyl-6-aryl pyridine derivatives were evaluated for their topoisomerase I and II inhibitory activities at 20 μM and 100 μM and cytotoxicity against several human cancer cell lines. Compounds 8, 9, 11–29 showed significant topoisomerase II inhibitory activity and compounds 10 and 11 showed significant topoisomerase I inhibitory activity. Most of the compounds (7–21) possessing 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety showed higher or similar cytotoxicity against HCT15 cell line as compared to standards. Most of the selected compounds displayed moderate cytotoxicity against MCF-7, HeLa, DU145, and K562 cell lines. Structure–activity relationship study revealed that 2-(5-chlorothiophen-2-yl)-4-(furan-3-yl) moiety has an important role in displaying biological activities.