Studies on antiplatelet agents from natural safrole. II. Synthesis and pharmacological properties of novel functionalized oxime O-benzylether derivatives

In an ongoing research program aiming at the synthesis and pharmacological evaluation of new possible prototype candidates exploring the molecular hybridation and bioisosterism principles for molecular designing, we describe in this paper the design and synthesis of a series of new functionalized oxime O-benzylethers (4a-b) and (14a-b) as antiplatelet agents based on the inhibition of arachidonic acid (AA) cascade enzymes. For the synthesis of these new bioactive derivatives we used safrole (5), a Brazilian abundant natural product, as starting material. The platelet anti-aggregating evaluation of these oxime O-benzylether compounds (4a-b) and (14a-b) in model induced by ADP, collagen and AA, has permitted to evidence an antithrombotic profile to these new derivatives, being the most active the derivative methyl [[3,4-methylenedioxyphenyl]methylene]amino]oxy]-4-methylenephenylacet ic acid (14a).     

Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity

Protein tyrosine kinases have been known to be involved in regulation of platelet aggregation, suggesting a potential target for antiplatelet therapy. Our previous study showed that 3,4-methylenedioxy-beta-nitrostyrene (MNS) prevented platelet aggregation caused by various stimulators, and this action was accompanied by inhibition of tyrosine kinases. In the present study, in order to examine the structural determinants required for the actions of MNS and to develop more potent tyrosine kinase inhibitors and antiplatelet agents, a new series of beta-nitrostyrene derivatives were synthesized and pharmacologically characterized. The beta-nitrostyrene derivatives inhibited thrombin- or collagen-induced human platelet aggregation, ATP secretion, GPIIb/IIIa activation and protein tyrosine phosphorylation. In recombinant enzyme assay, some beta-nitrostyrene derivatives also demonstrated potent inhibition of Src and/or Syk kinase activity. Furthermore, there was a good correlation between the inhibitory potency of these compounds on tyrosine kinases and on platelet activation/aggregation. Among them, a benzoyl ester derivative (compound 10) possess up to 8-fold greater potency than MNS and over two orders of magnitude greater potency than genistein or tyrphostin A47 in inhibiting platelet responses to thrombin. Our data suggest that beta-nitrostyrenes may represent a new class of tyrosine kinase inhibitors with potent antiplatelet activity.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

Synthesis, structure and biological evaluation of novel bicyclic nitroimidazole derivatives

A new series of 3-hydroxy-8-nitroimidazo[5,1-b]-1,4,5,6-tetrahydropyrimidine systems, being potential tuberculostatic agents, were synthesized. These products are close structural analogs of the basic structure of the known antitubercular bicyclic nitroimidazooxazine PA-824. The structures of the products obtained were confirmed by X-ray methods on the example of 3-hydroxy-8-nitro-1-phenylaminoimidazo[5,1-b]-1,4,5,6-tetrahydropyrimidine. Evaluation of these products for their anti-tuberculosis effects revealed interesting structure-activity relationships.     

Synthesis,molecular docking and antimicrobial evaluation of novel benzoxazole derivatives

In this research, previously and newly synthesized 5-amino-2-(4-substitutedphenyl/benzyl)benzoxazoles (3a–3l) and 2-substituted-5-(4-nitro/aminophenylsulfonamido)benzoxazoles (5a–5l, 6a–6l) were evaluated for their antimicrobial activities against Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212 and Mycobacterium tuberculosis H37RV ATCC 27294 and their drug-resistant isolates Candida albicans ATCC 10231 and Candida krusei ATCC 6258. The chemical structures of the newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, LC–MS and elemental analysis. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at the minimum inhibitory concentration (MIC) values between 256 and 8 µg/mL. Compounds 3a, 3c and 3f exhibited significant antimycobacterial activity showing MIC value of 8 µg/mL against both M. tuberculosis and its drug-resistant isolate. InhA, the enoyl-acyl carrier protein reductase from M. tuberculosis, is one of the key enzymes in the FASII system involved in mycobacterial fatty acid elongation cycle, which has been validated as an effective antimicrobial target. Molecular docking into active site of InhA was performed on 3FNE.PDB file to understand ligand–protein interactions. The compounds obtained from this research can be used as scaffolds in the design of new potent drugs.     

Synthesis,characterization and biological evaluation of some novel 2-substituted mercaptobenzimidazole derivatives.

Synthesis and biological assessment of six novel 2-substituted mercaptobenzimidazole derivatives is performed. The title compounds are characterized by their analytical and spectral data. All the synthesized compounds are screened for their anti-ulcer and anti-microbial activity. 2-(1H-benzimidazole-2-sulfinyl) –N-(4-benzyloxy-phenyl)-acetamide, N-(4-benzyloxy-phenyl)-4-(1H-benzimidazole-2-sulfinyl)-butyramide, N-(4-benzyloxy phenyl)-4-(5-methoxy 1H-benzimidazole-2-sulfinyl)-butyramide showed significant antiulcer activity. All the compounds moderate antibacterial and antifungal activity.     

Synthesis and cytotoxic evaluation of two novel anthraquinone derivatives

The antitumor activity of dihydroxyanthracenediones such as mitoxantrone on a panel of cancer cell lines during the last 30 years, led investigators to synthesize thousands of anthracycline analogs and test their cytotoxicity to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. To achieve this, new synthesized congeners either have different side arms or have extra rings on their skeletons. Following these studies, we proposed total synthesis of 2-amino-N-[4-(2-amino-3-hydroxy-propionylamino)-9,10-dioxo-9,10-dihydroanthracene-1-yl]-3-hydroxy-propionamide (V) and 6-amino-hexanoic acid [4-(5-amino-pentanoylamino)-9,10-dioxo-9,10-dihydro-anthracen-1-yl]-amide (VI). Acetylation of 1,4-diaminobenzene using acetyl chloride and reaction with phthalic anhydride under a Friedel-Crafts reaction and then cyclization gave 1, 4-diamino-anthraquinone. This compound was reacted with two amino acids (L-serine and 6-amino hexanoic acid) in their ester forms, using ethyl chloroformate as a coupling agent. Hydrolyzing esterified compounds gave their amino substituted derivatives. These compounds with diamine side arms are supposed to provide better intercalation with DNA. Synthesized novel ametantrone derivatives were tested against a panel of cancer cells (KB, Hela, MDA-MB-468 and K562), using MTT assay. The results showed that tested compounds inhibited the growth of cancer cells at micromolar concentrations. However, compound (VI) was more cytotoxic than compound (V) probably because of its longer side chains and better intercalation with DNA.     

Synthesis and antitumor evaluation of some novel pyrrolizine derivatives

Novel series of pyrrolizines (7, 9a–d, 10a–d, 11a, b, 14a–d, 16, 19, 20a, b, 24, 25a, b), pyrimido[5,4-a]pyrrolizines (12a, b, 13, 15a, b, 18, 21a, b, 22, 23a–d) and pyrido[3,2-a]pyrrolizines (17, 26a, b) were synthesized through different reactions. The chemical structures of all the synthesized pyrrolizine derivatives were determined by spectral and elemental analyses. Antitumor activity evaluation of all the prepared compounds was carried out using NR assay method against breast cancer cell line (MCF-7). The novel pyrrolizine scaffold 7 and all its prepared derivatives showed high antitumor activity comparable to that of doxorubicin.     

二氢哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的：合成新的哒嗪酮类化合物，并研究其抗血小板聚集活性。方法：在6-（4-氯乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮侧链引入不同取代的哌嗪，合成了一系列化合物，采用^1H-NMR、IR及元素分析等方法确证其结构。采用Born比浊法进行体外抗血小板聚集药理实验。结杲：合成的10个化合物都具有一定的抗血小板凝集的活性，其中化合物4的抗血小板聚集活性明显优于先导化合物MCI-154。结论：4-位取代哌嗪环基的引入对哒嗪酮类化合物抗血小板聚集的活性有显著影响。     

Synthesis and antimicrobial evaluation of novel urea derivatives from chromene based oxadiazole amines

A series of novel aryl ureides were synthesized based on oxadiazoles and different substituted aromatic amines. The intermediate amine, (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methanamines (6a) was reacted with aromatic amines in presence of triphosgene to obtain the urea derivatives 7a–d and 7e–i in high yields. The structures of all the intermediates and the final urea derivatives were established by IR, NMR and mass spectrometry data. The antibacterial activity of synthesized compounds was evaluated against two gram-negative bacteria namely Escherichia coli and Pseudomonas aeroginosa and it was observed that the urea derivatives 7a and 7i were promising antibacterial agents.     

Synthesis and pharmacological evaluation of novel thienopyrimidine and triazolothienopyrimidine derivatives

Novel tricyclic thienopyrimidines (2, 3, 5, 8) and triazole-fused tetracyclic thienopyrimidines (6a–c and 9a–c) were synthesized from the precursor 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (1). The structures of newly synthesized compounds were established by spectral and analytical data. The title compounds were screened for analgesic, anti-inflammatory, ulcerogenicity index, and antibacterial activities. Test compounds exhibited significant activity, the compounds (6a–c) and (9a–c) showed more potent analgesic activity, and the compounds (6c) and (9c) showed more potent anti-inflammatory activity than the reference standard Diclofenac Sodium. All the synthesized compounds exhibited remarkable antibacterial activity.     

Synthesis of pyranochromene and pyranopyrimidine derivatives from substituted natural coumarin isolated from Ammi majus L. and their biological evaluation

A series of novel coumarin derivatives were synthesized from 6-hydroxy-7-methoxy-4-methyl coumarin which was isolated from the aerial parts of the Egyptian medicinal plant Ammi majus L. (Apiaceae). The key intermediate 3-amino-5-methoxy-1-(4-methoxyphenyl)-10-methyl-8-oxo-1,8-dihydropyrano[3,2-f]chromene-2-carbonitrile (3c) was obtained in one-pot synthesis by treating α-cyanocinnamonitrile (1-c) with the natural compound: 6-hydroxy-7-methoxy-4-methyl coumarin (2). Chemical, elemental and spectroscopic evidences confirmed the structures of the synthesized compounds. Some of the newly synthesized compounds exhibited better anti-inflammatory activities at low concentrations compared with indomethacin as positive control.     

Synthesis and antibacterial evaluation of series of novel tri-substituted-s-triazine derivatives

Two novel series of s-triazine derivatives (6a–e and 7a–f) were synthesized with various aromatic and heterocyclic amines. The synthesized compounds were subsequently evaluated for their in vitro antibacterial activity against three gram-positive viz. Bacillus subtilis (NCIM-2063), Bacillus cereus (NCIM-2156), Staphylococcus aureus (NCIM-2079) and gram-negative bacteria viz. Pseudomonas aeruginosa (NCIM-2036), Escherichia coli (NCIM-2065) and Klebseilla pneumoniae (NCIM-2706) by the broth dilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) using streptomycin as reference standard. Structures of the synthesized compounds were elucidated on the basis of elemental analyses and spectral data.     

Synthesis and evaluation of novel spermidine derivatives as targeted cancer chemotherapeutic agents.

The utility of the spermidine moiety as the homing device for the selective delivery of chemotherapeutic and diagnostic agents into cancer cells was explored. Two spermidine analogs containing a cytotoxic agent were synthesized, N-[3,4-bis(benzyloxy)phenethyl]-N alpha-(3-amino-propyl)-L-ornithinamide trihydrochloride, 1a and N-[4-]bis(2-chloroethyl)amino]phenethyl]-N alpha-(3-aminopropyl)-L- ornithinamide tetrahydrochloride, 1b. These compounds were prepared from the fully protected spermidine molecule with a carboxyl group side chain, 8. The ability of the polyamine cytotoxic agents to inhibit B16-BL6 melanoma cell growth in culture was examined. The effects of pretreatment with DFMO on the activity of the synthesized compounds was also studied. The IC50 values of compounds 1a and 1b were on the same order of magnitude as the control compounds, N-acetyldopamine and chlorambucil, respectively. The inhibitory activities of compounds 1a and 1b were not enhanced by pretreatment with DFMO, suggesting that depletion of intracellular polyamines did not enhance the activity of these compounds.     

Synthesis and antitumor activity evaluation of novel ursolic acid derivatives

Eleven novel ursolic acid (UA) derivatives were designed and synthesized with modification at positions of C-2, C-3, and C-28 of UA. Their structures were confirmed by MS, ¹H NMR, and elemental analysis. Their in vitro cytotoxicities against various cancer cell lines (HeLa, HepG2, and BGC-823) were evaluated by MTT assay. The results indicated that all compounds could inhibit cell proliferation of HeLa, HepG2, and BGC-823 cells. Among them, compounds I₃ and I₄ showed more potent cytotoxicity on these three tumor cells than gefitinib (positive control), worthy to be studied further.     

氨基酸酯基二硫代甲酸酯类化合物的合成及体外生物活性评价

目的 合成18种氨基酸酯基二硫代甲酸酯类化合物(化合物1～18),并进行体外抗肿瘤活性以及抗乙肝病毒(HBV)活性评价.方法 以L-苯丙氨酸、L-丙氨酸、L-亮氨酸、L-异亮氨酸、L-谷氨酸及L-甘氨酸的甲酸酯为原料,通过碱催化,与CS2和卤代烷缩合反应,合成18种氨基酸酯基二硫代甲酸酯类化合物.化合物的结构及组成经过质谱、1H-NMR和熔点仪测试技术进行了表征.利用MTT法测定目标化合物1～18对子宫颈癌HeLa、肝癌HepG2、胃癌BGC-823、乳腺癌MCF-7、结肠癌SW-480细胞株的增殖抑制作用;ELISA法测定对HBsAg和HBeAg的抑制效果;实时荧光定量PCR法检测上清液中HBV DNA的表达量.结果 化合物11、12、17和18对上述5种肿瘤细胞株增殖有较好的抑制作用;相对于阳性对照拉米呋啶,化合物14和15能够较好的抑制HBV抗原的分泌和病毒DNA的复制.化合物14抑制HBV DNA、HBsAg和HBeAg的IC50值分别是0.43、0.28和0.1 mmol·L-1;化合物15的IC50值分别为0.24、0.02、0.03mmol·L-1.结论 这些二硫代甲酸酯类衍生物中,化合物11、12、17和18在体外具有抑制肿瘤细胞增殖的活性;化合物14和15在体外对HBV有较好的抑制作用.该研究为进一步开发二硫酯在抗肿瘤及抗病毒方面奠定了很好的基础.     

Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives

Ten novel oleanolic acid (OA) derivatives were synthesized through modifications at positions of A ring and C-28. Inhibitory activities of the oleanolic acid derivatives against SGC7901 and A549 cell lines were evaluated and confirmed by the tetrazolium bromidesalt (MTT) assay. The lab results revealed that all these compounds displayed some antitumor activity against SGC-7901 and A-549 cell lines. Among them, II₄ and II₅ exhibited excellent antitumor activities against SGC7901 cells and A549 cells, compared with gefitinib. Molecular docking studies have shown that compounds II₄ and II₅ produce potent antitumor activities by interacting with C-kit receptor through hydrogen bonds and hydrophobic bonds.     

Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic derivatives

This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized according to Gewald's conditions. The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated. Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1). The structures of the compounds were established based on the analytical and spectral data. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied.     

Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents

Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III _1–13 ) was confirmed by spectral characterization such as ¹H NMR, ¹³C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.     

Synthesis and anti-microbial evaluation of some novel 1,2,4-triazole derivatives

Triazoles with different substituent groups are found to possess diverse applications in the field of medicine and industry. A series of 4-(substituted ethanoyl)amino-3-mercapto-5-(4-nitro)phenyl-1,2,4-triazoles (NU-1 to NU-15) were synthesized as novel antimicrobial agents starting from 4-nitrobenzoic acid. The chemical structures of these newly synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, FAB+ -MS spectral data and elemental analysis. Their antimicrobial activities against Staphylococcus aureus (ATCC-25923), Pseudomonas aeruginosa (ATCC-27853), Escherichia coli (ATCC-8739), Bacillus substilis (ATCC-6633), Candida albicans (MTCC-227), Aspergillus niger (MTCC-3323) and Fusarium oxysporum (MTCC-2087) were investigated.