伯氨喹类似物的合成及其抗鼠疟活性

报道10个4-甲基-5-取代苯氧基-6-甲氧基-8-[(1-乙基-4-氨基)丁氨基]喹啉(10a～j)的合成及其抗疟活性。鼠疟初筛结果表明,有3个化合物对鼠疟 Plasmodium yoeli 的病因性预防作用较强,其中10c的活性可达伯氨喹的4～8倍;同时,10c也有较强的杀血液裂殖体活性,对鼠疟 Plasmodium berghei 的抑制性治疗作用以ED₅₀和ED₉₀计算,为伯氨喹的2倍,其余多数化合物活性与伯氨喹相当,少数不如伯氨喹。     

Synthesis of [13C6]primaquine

In support of a program to identify toxic metabolites of the antimalarial, primaquine, its [¹³C₆] analog was prepared from [¹³C₆] anisole in seven steps.     

Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents

Novel thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines were synthesized by a facile one‐pot multicomponent approach by the reaction of 2‐amino‐4‐methyl‐5‐acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l , showed moderate activity with half‐maximal inhibitory concentration (IC₅₀) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 μM against chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC₉₀ concentration of 12.5 µM in a stage‐specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.     

Synthesis of 4-hydroxycoumarin heteroarylhybrids as potential antimicrobial agents

A new series of 4-hydroxycoumarin derivatives 3a-d was synthesized by the reaction of 3-bromo-4-hydroxy coumarin 1 with various heteroaldehydes 2a-d in good yields. The synthesized compounds were characterized on the basis of their elemental and spectral (IR, (1)H-NMR and mass spectrometry) analysis. All target compounds were evaluated for their in-vitro antimicrobial activity against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, and Escherichia coli bacterial strains and fungal cultures of Candida albicans, Aspergillus fumigatus, Trichophyton mentagrophytes, and Penicillium marneffei by disk diffusion assay with slight modifications. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for reference standards. Among the tested compounds, 3a has shown the most potent antibacterial as well as antifungal activities.     

Synthesis and evaluation of pyridinium‐hydrazone derivatives as potential antitumoral agents

The hydrazones of 4‐hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF‐7, PC3, U2OS, and HEK293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems showed high cytotoxic activity (IC₅₀ = 3.27–8.54 μm ) on cancer cells. 3d (4‐(2‐(4‐hydroxybenzylidene)hydrazinyl)‐1‐(4‐phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC₅₀ value of 3.27 μm against MCF‐7. The most active derivatives ( 1d , 2d , 3d , 4 , and 5 series) were selected to investigate for the effects on autophagy by analyzing the expression of autophagy marker proteins. The conversion of LC3‐I to its lipidated form LC3‐II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d induced lipidated form LC3‐II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting as the autophagy inhibition results in accumulation of p62. Further molecular mechanistic studies including morphological analysis and live–death assays indicated that all tested compounds ( 1d , 2d , 3d , 4 , and 5 series) are potent antitumoral molecules and all except for 3d have potential to inhibit autophagic flux.     

Synthesis of new arylisoxazole–oxindole conjugates as potent antiproliferative agents

A new series of arylisoxazole–oxindole derivatives ( 6a–r ) were synthesized and evaluated for their antiproliferative activity against human cancer cell lines including non‐small cell lung (A549), cervical (HeLa), breast (MCF‐7), and prostate (DU‐145) cancer cell lines. The synthesized compounds ( 6a–r ) demonstrated excellent to moderate cytotoxicity with IC₅₀ values ranging from 0.82 to 3.69 μm . Some new compounds ( 6m–r ) exhibited profound cytotoxicity better or similar to positive control. More particularly, the compound 6q possesses donating substituent like methoxy group presented at 5‐position on D ring exhibited remarkable antiproliferative activity against A‐549 (lung cancer) with an IC₅₀ value 0.82 μm . Further studies to determine the mechanistic aspects of these conjugates are under progress.     

Design and synthesis of new 2‐anilinoquinolines bearing N‐methylpicolinamide moiety as potential antiproliferative agents

A series of new 2‐anilinoquinolines 6a – o possessing the substantial N‐methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF‐7, SK‐BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c , 6d , 6j , 6k , and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five‐dose testing mode to determine their GI₅₀ values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4‐chloro‐3‐trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI₅₀ values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA‐MB‐468, renal A498, and melanoma SK‐MEL‐5 and UACC‐62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF‐1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B‐Raf^V600E and C‐Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.     

Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.     

Synthesis of some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents

Chalcones of 2a–f and their corresponding products, pyrazolines 3a–f , were synthesized and evaluated for their anti‐inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti‐inflammatory activity. The most active compounds of this series, 2a , 2b , and 2d , were found to be most potent. They showed higher percentage of inhibition of edema than the standard drug indomethacin.     

Synthesis of radiolabeled O6‐benzylguanine derivatives as new potential PET tumor imaging agents for the DNA repair protein O6‐alkylguanine‐DNA alkyltransferase

Novel radiolabeled O⁶‐benzylguanine derivatives, 2‐amino‐6‐O‐[¹¹C]‐[(methoxymethyl)benzyloxy]‐9‐benzyl purines ([¹¹C]p‐O⁶‐AMBP, 1a ; [¹¹C]m‐O⁶‐AMBP, 1b ; [¹¹C]o‐O⁶‐AMBP, 1c ), have been synthesized for evaluation as new potential positron emission tomography (PET) tumor imaging agents for the DNA repair protein, O⁶‐alkylguanine‐DNA alkyltransferase (AGT). The appropriate precursors for radiolabeling were obtained in three steps from starting material 2‐amino‐6‐chloropurine with moderate to excellent chemical yields. Tracers were prepared by O‐[¹¹C]methylation of hydroxymethyl precursors using [¹¹C]methyl triflate. Pure target compounds were isolated by solid‐phase extraction (SPE) purification procedure in 45–60% radiochemical yields (decay corrected to the end of bombardment), and a synthesis time of 20–25min. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Synthesis and biological evaluation of some novel 1,4-dihydropyridines as potential antitubercular agents

Recent studies showed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have significant antitubercular activity. In this study, we have synthesized new derivatives of 1,4-dihydropyridines bearing carbmethoxy and carbethoxy group at C-3 and C-5 of the 1,4-dihydropyridine ring. In addition, 1H-pyrazole ring is substituted at C-4 position. These analogues were synthesized by multi-component Hantzsch reaction. The in vitro antitubercular activity of compounds against Mycobacterium tuberculosis H(37) Rv was evaluated. The lowest minimum inhibitory concentration value, 0.02 μg/mL and SI > 500, was found for dimethyl 1,4-dihydro-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethylpyridine-3,5-dicarboxylate 3f, diethyl 1,4-dihydro-4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethylpyridine-3,5-dicarboxylate 4c and diethyl 1,4-dihydro-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl pyridine-3,5-dicarboxylate 4e, making them more potent than first-line antitubercular drug isoniazid. In addition, these compounds exhibited relatively low cytotoxicity.     

Synthesis,characterization and pre‐clinical evaluation of 99mTc‐tricarbonyl complexes as potential myocardial perfusion imaging agents

Myocardial perfusion imaging is an established Nuclear Medicine investigation. Current myocardial perfusion imaging agents sestamibi and tetrofosmin have number of drawbacks; low heart uptake coupled with uptake into the surrounding tissues leads to a poorer image quality. There is a need for continued research into designing and evaluating potentially superior myocardial imaging agents. Tri‐carbonyl‐technetium and rhenium complexes were prepared by combination with mono‐dentate and bi‐dentate ligands. Complexes were characterized by HPLC, MAS, nuclear magnetic resonance, infrared, single‐crystal X‐ray diffraction and partition coefficient determinations. ^99mTc(CO)₃ complexes were administered intravenously to Sprague Dawley rats, and tissue distribution studies were carried out at 15 min and 1 h p.i. Radiochemical purity was assessed as >90%. 1‐10‐phenanthroline, 2,2′‐bipyridine and imidazole complexes gave the highest heart uptake. The percentage injected dose per gram (n = 3) at 1 h for 1‐10‐phenanthroline/imidazole was blood 0.21 ± 0.01, heart 1.12 ± 0.11, kidney 3.61 ± 1.13, liver 0.62 ± 0.06, lung 0.28 ± 0.12, spleen 0.24 ± 0.05, small intestine contents 1.87 ± 0.92; and for 2,2′‐bipyridine /imidazole was blood 0.23 ± 0.02, heart 1.07 ± 0.18, kidney 3.31 ± 1.28, liver 0.56 ± 0.09, lung 0.14 ± 0.02, spleen 0.2 ± 0.1, small intestine content 1.05 ± 0.48. Further investigation to evaluate more complexes based on 1,10‐phenanthroline, 2,2′‐bipyridine and imidazole derivatives could potentially lead to agents with an increased heart uptake and faster clearance from the liver and gastrointestinal tract.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

Synthesis and cellular uptake of p‐[123I]‐phenyl‐amino‐thiazole (123I‐PAT) as a potential agent for targeting tubulin polymerization in tumors

The phenyl‐amino‐thiazole (PAT) templates of methoxylbenzoyl‐aryl‐thiazole are potent agents against cancer by inhibiting tubulin polymerization in the nanomolar range. Herein, a radioiodinated PAT, [¹²³I]‐PAT 1, was prepared via a tributylstannyl precursor and [¹²³I]iodide through electrophilic aromatic radioiodination. Radiolabelling of [¹²³I]‐PAT 1 was achieved in less than 15 min, with a radiochemical purity of over 99%. The accumulated radioactivity in tumor cellular uptake experiments suggested that [¹²³I]‐PAT could serve as a potential radioprobe for targeting tumor cells.     

Synthesis and biodistribution studies of iodine‐131 D‐amino acid YYK peptide as a potential therapeutic agent for labeling an anti‐CD20 antibody

A major drawback of conventionally radioiodinated monoclonal antibodies for radioimmunotherapy is in vivo dehalogenation of iodine as a result of deiodinase recognition. To solve this problem we have synthesized a YYK tri‐peptide consisting of non‐metabolizable D ‐amino acids modified with the N‐succinimidyl (N‐Succ) function. The chemical purity of the synthesized peptide as assessed by analytical high performance liquid chromatography was 95%. Labeling of the Fmoc‐D ‐Tyr(_tBu)‐D ‐Tyr(_tBu)‐D ‐Lys(Boc)‐N‐Succ was performed using the chloramine‐T method and the conventional extraction, resulting in a radiochemical yield of 50–71% and a radiochemical purity of >95%. Radioiodination of the peptide was followed by conjugation to anti‐CD20 antibody with 65–75% labeling efficiency and 90% radiochemical purity. The effect of radioiodinated peptide on the biological behavior of the conjugate was evaluated through biodistribution studies in normal Lewis rats. Thyroid and stomach levels from Rituximab labeled with [¹³¹I]‐YYK‐peptide were two‐ to four‐fold less than those with directly labeled [¹³¹I]‐Rituximab, suggesting low recognition of its D ‐iodotyrosine residue by endogenous deiodinases. The favorable in vitro/in vivo stability and biodistribution profiles suggest that this radioiodine‐labeled YYK peptide is a good candidate for further exploration of its potential clinical application. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of New N‐Substituted 5‐Arylidene‐2,4‐thiazolidinediones as Anti‐Inflammatory and Antimicrobial Agents

A novel series of 5‐arylidene ‐ 2,4‐thiazolidinediones (TZDs) 2a – p was synthesized from the condensation of 3‐((2‐phenylthiazol‐4‐yl)methyl)thiazolidine‐2,4‐dione with different benzaldehyde derivatives. All the structures were confirmed by their spectral (IR, ¹H NMR, ¹³C NMR and mass) and elemental analytical data. The new molecules were evaluated in vivo as anti‐inflammatory agents in an acute experimental inflammation, evaluating the acute phase bone marrow response and phagocyte activity. All compounds, excepting one, reduced the absolute leukocytes count due to the lower neutrophil percentage. Phagocytary index was decreased by the same molecules, while only half of them reduced the phagocytary activity. The effect was superior to meloxicam, the reference anti‐inflammatory drug, for the majority of the TZD derivatives. The new molecules were also investigated for their antimicrobial properties on Gram‐positive and Gram‐negative bacteria and one fungal strain. Two compounds ( 2e and 2n ) manifested growth inhibition capacity on all the tested strains.     

Carbon‐14 radiolabelling and tissue distribution evaluation of a potential anti‐TB compound

This paper describes a five‐step synthesis of a carbon‐14‐labelled pyrazole compound (11). A total of 2.96 MBq of 11 was obtained with the specific activity of 2242.4 MBq/mmol. The radiochemical purity was >99%, and the overall radiochemical yield was 60% based on the [¹⁴C₆] 4‐bromoaniline starting material. Biodistribution results showed that the radiotracer (administrated orally) has a high accumulation in the small intestine, large intestine and liver of both non‐infected and tuberculosis (TB)‐infected mice. Therefore, this suggests that compound 11 undergoes hepatobiliary clearance. The compound under investigation has been found to be slowly released from the liver between 2 and 8 h. The study revealed that 11 has no affinity for TB cells.     

Synthesis, structural characterization and biological evaluation of novel [1,2,4]triazolo [1,5-b][1,2,4]benzothiadiazine-benzothiazole conjugates as potential anticancer agents

Two series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine 2-methyl/ethyl sulfanyl benzothiazole derivatives (5a-d) and 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4] benzothiadiazine 2-phenoxy benzothiazole derivatives (16a-c) were synthesized and their structures confirmed by NMR, MS, IR and X-ray crystallography. These compounds were evaluated for their cytotoxicity against 60 human tumour cell lines. One of the synthesized compounds (5b) exhibited significant inhibitory activity against most of the cell lines and has been further evaluated for the five-dose screening.     

Synthesis of [18F]‐labeled adenosine analogues as potential PET imaging agents

The syntheses of adenosine analogues, 2′‐deoxy‐2′‐[¹⁸F]fluoro‐9‐β‐D ‐arabinofuranosyladenine ([¹⁸F]‐FAA) and 3′‐deoxy‐3′‐[¹⁸F]fluoro‐9‐β‐D ‐xylofuranosyladenine ([¹⁸F]‐FXA) are reported. Adenosine ( 1 ) was converted to its methoxytrityl derivatives 2 and 3 as a mixture. After separation, these derivatives were converted to their respective triflates 4 and 5 . Each triflate was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6b or 7b , which by acidic hydrolysis yielded compounds 8b and 9b . Crude preparations were purified by HPLC to obtain the desired pure products. The radiochemical yields were 10‐18% decay corrected (d. c.) for 8b and 30‐40% (d. c.) for 9b in 4 and 3 runs, respectively. Radiochemical purity was >99% and specific activity was >74 GBq/μmol at the end of synthesis (EOS). The synthesis time was 90‐95 min from the end of bombardment (EOB). Copyright © 2003 John Wiley & Sons, Ltd.