Kinesin Spindle Protein Inhibitors with Diaryl Amine Scaffolds: Crystal Packing Analysis for Improved Aqueous Solubility

相似文献   

β-四氢咔啉衍生物的合成和生物活性

纺锤体驱动蛋白(kinesin spindle protein，KSP)是有丝分裂过程中二极纺锤体形成和维持所必需的。抑制KSP的功能将导致细胞周期停滞和细胞编程性细胞死亡，并且不干扰微管的其他功能，因而可成为潜在的肿瘤治疗靶点。本文合成了β-四氢咔啉衍生物作为新型的KSP抑制剂，并测定了其对KSP的抑制活性，均优于阳性对照物。     

Kinesin spindle protein Inhibitors as anticancer agents

Kinesin spindle protein (KSP), or Hs Eg5, is a member of the kinesin superfamily of molecular motor proteins that utilise the energy generated from the hydrolysis of ATP to transport vesicles, organelles and microtubules. KSP plays essential roles in mitotic spindle function and its inhibition prevents normal bipolar spindle formation, leading to mitotic arrest and subsequently to apoptosis of cells. Therefore, KSP inhibitors have potential as novel anticancer therapeutics. Since the discovery of monastrol in 1999, many types of KSP inhibitors have been reported. This review describes the mechanism of action and development of different types of KSP inhibitors.     

Synthesis and pharmacological activities of some novel 5-chloro-N-(4-(1,5-(disubstituted)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-2-methoxybenzamide derivatives

A series of substituted pyrazole derivatives were prepared from N1-[4-(cinnamoyl) phenyl]-5-chloro-2-methoxybenzamides 2a–c, which were prepared from N-(4-acetylphenyl)-5-chloro-2-methoxybenzamide as starting material. Treating of compound 2a–c with methylhydrazine or phenylhydrazine afforded the corresponding N-substituted pyrazoline derivatives 3a–c and 4a–c, respectively. The acryloyl derivatives 2a–c were reacted with hydrazine hydrate in dioxane afforded a pyrazoline 5a–c, which was acetylated with acetyl chloride in dioxane to yield the N-acetyl analogue 6a–c. In addition, pyrazoline 5c was reacted with morpholine in the presence of paraformaldehyde to give the corresponding N-substituted pyrazoline derivative 7. The structure assignments of the new compounds are based on chemical and spectroscopic evidence. The pharmacological screening showed that many of these compounds have less toxicity and good anti-inflammatory activities.     

Structure-activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors

The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated. β-Carboline and lactam-fused carbazole derivatives exhibited remarkably potent KSP inhibitory activity and mitotic arrest in prometaphase with formation of an irregular monopolar spindle. The planar tri- and tetracyclic analogs inhibited KSP ATPase in an ATP-competitive manner just like biphenyl-type inhibitors.     

Novel derivatives of 5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid: their synthesis,antimicrobial, antifungal,and urease inhibitory studies

Sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid is an orally active synthetic, broad spectrum third generation quinolone, with excellent activity against Gram-positive bacteria with selectivity against anaerobes and atypical pathogens. Three derivatives of SPFX (2, 3, and 4) were synthesized by reacting different aromatic carboxylic acids with SPFX (1). Chemistry involved the formation of amide between reacting species through nucleophilic substitution reactions. The synthesized derivatives were then structurally characterized by IR, NMR, and mass spectroscopic techniques. The antimicrobial activities of these derivatives were evaluated against four Gram-positive, seven Gram-negative bacteria, and six fungi, using SPFX as a reference. Statistical analysis revealed these derivatives as active antimicrobial agents, and 2 was more potent antimicrobial agents than the parent drug as well other fluoroquinolones. Compounds 3 and 4 showed a significant activity against Fusarium solani. Moreover, these three derivatives were evaluated for inhibitory activities against enzyme urease, carbonic anhydrase II, and α-chymotrypsin. Results showed their selectivity against urease enzyme. Based on their nontoxic behavior, these derivatives may be potential agents for further studies.     

Synthesis,characterization, and screening for analgesic and anti-inflammatory activities of new 1,3,4-oxadiazole derivatives linked to quinazolin-4-one ring

In the present study, several new 1,3,4-oxadiazole derivatives linked with quinazolin-4-one moiety were synthesized by following steps. 2-methyl -4H-3, 1-benzoxazin-4-one, and 2-phenyl -4H-3, 1-benzoxazin-4-one were synthesized in the first and second step by stirring anthranilic acid in pyridine with benzoyl chloride and with an acetic anhydride for 30?min at room temperature. On treatment with semicarbazide with the above synthesized intermediates, that is, 2-methyl-4H-3,1-benzoxazin-4-one, and 2-phenyl-4H-3,1-benzoxazin-4-one in the third step afforded 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide. These were introduced in cyclization reaction with different aromatic acids, aromatic aldehydes, and carbon disulfide in the next step, producing the corresponding 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-phenyl-quinazolin-4(3H)-one derivatives, 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-quinazolin-4(3H)-one derivatives, 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one derivatives and 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-methylquinazolin-4(3H)-one derivatives. Purity of these synthesized derivatives was confirmed by thin layer chromatography, melting point. Structure of the derivatives was set up by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats. In animal studies, the derivatives 3-[4-acetyl-5-(2-hydroxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one shown more potent analgesic activity and the derivatives 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-methylquinazolin-4(3H)-one shown more potent anti-inflammatory activity as compared to other derivatives. The results of current study indicate that cyclization of carbohydrazide group of intermediate 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide with different aromatic acids, aromatic aldehydes, and carbon disulfide produces novel quinazolin-4-one linked oxadiazole derivatives with potent analgesic and anti-inflammatory activities.     

Design and synthesis of niflumic acid-based N-acylhydrazone derivatives as novel anti-inflammatory and analgesic agents

A new series of niflumic acid-based N-acylhydrazone derivatives 5a–p were synthesized and evaluated for their anti-inflammatory and analgesic activities. Most of the compounds have shown anti-inflammatory activity with a moderate-to-excellent activity range (20–80 % reduction in inflammation). Among them, 3-chlorophenyl 5d and 3-pyridyl derivatives 5o exhibited the most potent anti-inflammatory activity relative to niflumic acid as the reference drug (77, 76, and 70 % reduction in inflammation at 1-h postdrug administration, respectively). Also, molecular simplification of niflumic acid through replacing the N-aryl group with N-methyl group produced compounds 6a–f with anti-inflammatory activity in a quite similar manner to those of their parent derivatives. In this subgroup, 4-pyridyl derivative 6f showed the most potent anti-inflammatory activity relative to niflumic acid (80 % reduction in inflammation at 1-h postdrug administration). The compounds with highest anti-inflammatory activity were subjected to analgesic assays and showed moderate-to-excellent analgesic activities. The compound 5j, 4-methoxy derivative, exhibited the highest analgesic activity relative to niflumic acid (97 and 68 % activity, respectively).     

Synthesis,characterization of 4,6-disubstituted aminopyrimidines and their sulphonamide derivatives as anti-amoebic agents

The present study describes the synthesis and anti-amoebic activity of 4,6-disubstituted aminopyrimidines (1b–10b) and their sulphonamide derivatives (1–20). All the desired compounds were characterized by spectral data and their purity was confirmed by elemental analysis. The aim of the study was to explore the effect of the target compounds on in vitro growth of HM1:IMSS strain of Entamoeba histolytica. In vitro anti-amoebic activity was performed by microdilution method and the results were compared with standard drug metronidazole. The results revealed that sulphonamide derivatives (1–20) showed better activity than 4,6-disubstituted aminopyrimidines (1b–10b). 5 pyrimidine and 12 sulphonamide derivatives were better inhibitors of the growth of E. histolytica than the reference drug metronidazole (IC₅₀ = 1.80 μM). The promising in vitro anti-amoebic activity of the compounds make them promising molecules for further lead optimization in the development of novel anti-amoebic agents, therefore, it is hoped that these preliminary results could help in designing better molecules with an enhanced anti-amoebic activity.     

Three acetophenones from Acronychia pedunculata

Phytochemical investigation of the leaves and twigs of Acronychia pedunculata has led to the isolation of three new acetophenone monomers 1–3 as well as 1-[2′,4′-dihydroxy-3′,5′-di-(3″-methyl-2″-butenyl)-6′-methoxy]phenylethanone (4), acronyculatin E (5), a mixture of β-sitosterol and stigmasterol, and sesamin. The structures of these new compounds were elucidated spectroscopically. The inhibitory activities of the isolated acetophenone derivatives against mammalian DNA polymerases and human cancer cell growth were also assessed.     

The synthesis of 6-(N-Arylamino)-7-chloro-5,8-quinolinedione derivatives for evaluation of antifungal activities

A series of 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives was newly synthesized for the evaluation of antifungal activities. 5-Amino-8-hydroxy-quinoline (II) was treated with KClO₃ in HCl to give 6,7-dichloro-5,8-quinolinediones (III). 6-(N-arylamino)-7-chloro-5,8-quinolinediones1–12 were prepared by regioselective nucleophilic substitution of III with arylamines. In the presence of CeCl₃, the N-arylamino groups were introduced at the 6-position of 5,8-quinolinedione ring by the regioselective substitution. These derivatives1–12 were tested for antifungal and also antibacterial activities,in vitro, againstCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus andEscherichia coli. The MIC values were determined by the two-fold agar/streak dilution method. Newly obtained 6-(N-arylamino)-7-chloro-5,8-quinolinedione derivatives showed potent antifungal and antibacterial activities. Among these derivatives,1, 3, 5, 7, 8 and9 showed more potent antifungal activities than fluconazole and griseofulvin. Also most of derivatives were found to be more active than ampicillin against gram-positive bacteria.1 and7 showed the very potent antifungal activities.1 was the most effective in preventing the growth ofCandida albicans, Aspergillus niger, Tricophyton mentagrophytes, Bacillus subtilis andStaphylococcus aureus at MIC 1.6 μg/ml.     

Acid promoted intramolecular formation of 3,5-anhydro-1,4-furano-7-ulose derivatives via the Wittig-cyclization procedure and their antimicrobial properties

We report a convenient method for the synthesis of 3,5-anhydrofuranose derivatives. Formation of the 3,5-anhydro (oxetane) rings was achieved by the Wittig-cyclization procedure under acid promoted conditions starting from 5(E)-eno-1,4-furano-7-ulose derivatives (1, 4, and 7). Unprotected hydroxyl groups on C-3 of the furanose rings added intramolecularly to the acyclic double bond under very mild acidic conditions in methanol to form the stereoisomeric 3,5-anhydro derivatives in good yields. The products (2, 3, 5, 6, and 8) were found to exhibit antibacterial properties. The reaction was found to be strongly solvent dependent as use of methanol instead of chloroform afforded 5-acetylmethyl-furfural 9 as a major product instead of the expected oxetane. All of the synthesized compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC6538-P, Bacillus subtilis ATCC 6633, Salmonella typhimurium CCM 5445, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 12228, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae CCM 2318, and Candida albicans ATCC 10239 and exhibited a range of activities against selected microorganisms.     

Derivatives of Dexanabinol. I. Water-Soluble Salts of Glycinate Esters

Purpose. Glycinate ester-type water soluble derivatives of dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners. Methods. Conventional procedures were used for the synthesis of the novel derivatives. Stability studies in water and blood (rat, dog, human) were performed by HPLC; NMDA receptor binding was determined by radio ligand [³H] MK-801 -displacement; the neuro-protection and neurotoxicity studies were performed in cortical cell cultures. Results. Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl-and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were relatively soluble and stable in water. The quaternary ammonium salt-type derivatives rapidly hydrolyzed to the parent drug in various types of blood including human. In vitro activity studies indicated that the novel derivatives possess NMDA receptor binding properties. The neuroprotecting properties manifested by some of the new derivatives were associated with very low neuronal cell toxicity and are credited to parent compound released by hydrolysis during the experiments rather than to intrinsic activity. Conclusions. Compounds 7 and 8 are promising water-soluble pro-drug candidates for 1; the glycinate ester 3 might be used as an active analog.     

Synthesis and characterization of novel benzo[d][1,3]dioxole gathered pyrazole derivatives and their antimicrobial evaluation

Benzo[d][1,3]dioxole gathered pyrazole derivatives (4a–i) were synthesized by the reaction of chalcones with phenyl hydrazine in presence of absolute alcohol as a solvent. Chalcones were prepared by the Claisen-Schmidt reaction between 1-(benzo[d][1,3]dioxol-5-yl)ethanone (2) and substituted aromatic aldehydes. The synthesized compounds were characterized by spectral and elemental analysis data. Furthermore, Benzo[d][1,3]dioxole gathered pyrazole derivatives (4a–i) were evaluated for their in vitro antimicrobial activity. Among the newly synthesized compounds 4a, 4c, 4 g and 4 h showed the excellent antifungal activity and as well as 4a and 4d showed the excellent antibacterial activity when compared to other compounds.     

Synthesis,antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study

The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16 µg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2 µg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.     

Design, synthesis, and biological evaluation of new 4-thiazolidinone derivatives substituted with benzimidazole ring as potential chemotherapeutic agents

In search of novel antiviral and anticancer agents with promising pharmacotoxicological profile, a study was initiated to synthesize new 2-thioxo-4-thiazolidinones as well as 2-phenylimino-4-thiazolidinones substituted with benzimidazole ring system. The compounds were screened primarily for their antiviral as well as anticancer activities. The synthesis of some novel 5-substituted thiazolidinones was also described. None of the tested compounds showed inhibitory activity against Hepatitis C virus replication. Two 2-phenylimino-4-thiazolidinone derivatives (9a and 10) exhibited significant antiproliferative activity against human colon carcinoma cell line HCT 116 and human hepatocellular carcinoma HEPG2 cell line, respectively. Results also indicated that six thiazolidinone derivatives (5a, 5d, 5e, 5f, 5h, and 9d) showed moderate antiproliferative activity against human breast adenocarcinoma cell line MCF7 in comparison to the standard drug Doxorubicin. Moreover, a docked pose of the most potent three cytotoxic compounds 5a, 5h, and 9d against MCF7 was obtained bound to Human N-acetyl transferase1 NAT1 binding pocket by molecular operating environment module.     

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.     

Synthesis and antibacterial evaluation of 3,3′-diindolylmethane derivatives

Various 3,3′-diindolylmethane (DIM) derivatives were synthesized and the antibacterial activity of these compounds were tested against ten bacterial strains and their minimum inhibitory concentration (MIC) values were determined. The MIC values of derivatives 3a–d and 5a–e were ranging from 125 to 500 μg/mL. Among these derivatives, 2-(di(1H-indol-3-yl)methyl)phenol (5a) and 3-((1H-indol-3-yl)(pyridin-3-yl)methyl)-1H-indole (5d) exhibited potent activity, showing MIC values 6.5–62.5 μg/mL against Gram positive and Gram negative bacteria. Hemolytic assay of these active DIM derivatives did not show considerable toxic effect on the normal human erythrocytes.     

Antitumour activity of 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-triones against Dalton’s ascitic lymphoma in mice

A new series of novel benzimidazole derivatives containing barbitone moiety (5a–f) was synthesized by a Knoevenagel condensation of (2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a–f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, ¹H NMR and mass spectra analysis. Acute toxicity studies were performed initially to determine the safety of titled derivatives and the ED ₅₀ value was calculated 50 mg/kg. All the final derivatives were screened for antitumour activity against Dalton’s ascitic lymphoma in mice. All the new candidates at a dose of 50 mg/kg showed a good antitumour activity against DLA-bearing mice when compared to the standard 5-fluro uracil. Among the final derivatives (5e), 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-(3-nitrophenyl) prop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-trione was found to be most potent antitumour in nature.     

Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5-(5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylori agents

Background and the purpose of the study

Helicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test.

Methods

The title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole.

Results and discussion

The results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5-nitrothiophen counterpart.

Conclusion

The most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4-thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 μg/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori.