Synthesis and evaluation of the analgesic and antiinflammatory activities ofO-Substituted salicylamides

The present investigation deals with the synthesis of some new salicylamidoacetyl sulfonamides 3a,b, salicylamido ethylacetate 4, salicylamido acetic acid hydrazide 5, which is considered as the key intermediate for the synthesis of several series of new compounds such as salicylamido pyrazol 6 and pyrazolone 7. N-imido-derivatives 9, 10, 11, thiadiazole 13, oxadiazole 14, 15, Schiffs bases 16a-f. Cyclocondensation of Schiffs bases with thioglycolic acid gave thiazolidinone 18a-c while with acetylchloride afforded azitidinones 19a-c and with acetic anhydride gave 1,4-benzoxazepine-3,5-dione. Some of the compounds were tested for their analgesic and antiinflammatory activities as well as ulcerogenic effects. Some derivatives were more effective than salicylamide and ulcerogenic activity was variably lowered.     

Synthesis and evaluation of hydroquinone derivatives as inhibitors of Isocitrate Lyase

Isocitrate lyase (ICL) is envisaged as an attractive drug target for the development of antimicrobial agents. We have prepared a series of hydroquinone derivatives on the basis of the structure of halisulfates, a naturally occurring inhibitor of ICL. The obtained derivatives were evaluated against ICL of C. albicans. The preliminary structure-activity relationships and the minimal structural requirements for potency were established through structural modifications.     

Synthesis of novel benzofuran and related benzimidazole derivatives for evaluation ofin vitro anti-HIV-1, anticancer and antimicrobial activities

Previously, we synthesized and evaluated several benzofuran derivatives containing heterocyclic ring substituents linked to the benzofuran nucleus at C-2 by a two- to four-atom spacer as potential anti-HIV-1, anticancer and antimicrobial agents. Among these derivatives, NSC 725612 and NSC 725716 exhibited interesting anti-HIV-1 activity. To further investigate the structure-activity relationship, we synthesized several new benzofuran derivatives derived from 2-acetylbenzofuran (2, 3a-c) and 2-bromoacetylbenzofuran (6; 7a,b; 8a,b). The compounds were designed to comprise the heterocyclic substituents directly linked to the benzofuran nucleus at C-2. Moreover, various related benzimidazoles derived from 2-acetylbenzimidazole and from 2-cyanomethylbenzimidazole (12a,b; 13a,b; 15; 16a,b) were also prepared as isosteres. The synthesized compounds were preliminarily evaluated for their in vitro anti-HIV-1, anticancer and antimicrobial activity. Compounds 2, 3a, 3b, and 12b showed weak anti-HIV-1 activity. Compound 6 exhibited mild activity against S. aureus, while compound 15 had mild activity towards S. aureus and C. albicans. However, no significant anticancer activity was observed with any of the tested compounds. From these results, we conclude that the presence of the spacer between the heterocyclic substituent and the benzofuran nucleus may be essential for the biological activity.     

Synthesis of new pyrimidine derivatives with evaluation of their anti-inflammatory and analgesic activities

5-Formyl-6-aminopyrimidine-2,4-(1H, 3H)-dione (2) has been previously prepared fromcompound 1. Cyclocondensation reaction of compound 2 with cyanoacetamide gave substituted pyridopyrimidine 3. Also, compound 2 was condensed with p-amino acetophenone and hydrazine derivatives to give 5-([(4-acetylphenyl)imino]methyl)-6-aminopyrimidine (4) and 5-substituted carboaldehyde-6-amino pyrimidine derivatives (5a-d), respectively. Moreover, cyclocondensation reaction of compound 2 with thiosemcarbazide and semicarbazide hydrochloride gave 5-(5-thioxo or oxo-triazol-3-yl)-6-amino pyrimidine (6) and (7), respectively. Cyclocondensation reaction of compound 2 with thiourea and ethyl acetoacetate led to the formation of substituted ethyl bipyrimidine-5-carboxylate 8. Also, compound 2 was reacted with acetoacetic acid hydrazide and 2-cyanoacetohydrazide to give 5-(acetylpyrazol-6-aminopyrimidine 9 and 3-(6-aminopyrimidine-5-yl) pyrazole-4-carboxamide 10, respectively. Furthermore, compound 1 was diazotized to afford the diazonium salt 11. Its coupling with ethyl acetoacetate, ethyl cyanoacetate, acetylacetone, malononitrile, cyanoacetamide, diethylmalonate, in sodium acetate buffered solution afforded substituted hydrazonopyrimidines: ethylhydrazono-3-oxobutanoate 12, ethylhydrazono-3-oxopropanoate 13, pentane-2,3,4-trione hydrazone 14, cyanohydrazonoacetamide 15, diazenyl malonamide 16 and diethylhydrazonomalonate 17, respectively. Moreover, substituted pyrazolediazenylpyrimidine derivatives 18a,b, 19a,b, 20, 21a-c, 22 were synthesized by the cyclization of substituted hydrazonopyrimidines 12, 17, 15, 14 and 13, respectively. The analgesic and anti-inflammatory activities of some of the synthesized compounds were evaluated. Compounds C18a, C20, C21b and C22 showed the most significant analgesic effects among synthesized moieties. All tested compounds, nonetheless, C18b showed significant anti-inflammatory effect in carrageenan induced paw edema model.     

Synthesis, spectroscopic characterization, stability assessment and DNA-binding of new 2,6-piperidinedione derivatives.

This work reports on structural characterization of new antineoplaston (ANP) representatives, namely 3-(benzoylamino)-2,6-piperidinedione (BPD), 3-(4-methoxybenzoylamino)-2,6-piperidinedione (MPD) and 3-(p-nitrobenzoylamino)-2,6-piperidinedione (NPD). These compounds were prepared by reacting N-(4-substituted benzoyl)-glutamines with N-hydroxysuccinimide to afford the corresponding esters, which were heated to produce the corresponding 2,6-piperidinedione (PD) compounds. Non-destructive analytical procedures such as 1H NMR and NIR analyses confirmed the postulated chemical structures of these PD compounds. HPLC chromatograms at an ambient temperature or from solutions preheated at 30, 40 or 60 degrees C displayed only a single peak for each compound. Combination of heat with pH modification had virtually no effect on the obtained peaks, thus attesting to the stability and purity of these compounds. MS analysis displayed molecular mass ions indicative of BPD, MPD and NPD at m/z 233.4, 263.2 and 278.3, respectively. The fragmentation patterns using MS/MS analyses conformed to the structural and molecular formulae of the prepared compounds. Furthermore, preliminary biological assessments showed the capacity of these compounds to bind to the DNA. NPD, but not BMP or MPD, had a superior affinity to the DNA than the prototype ANP-A10.     

Synthesis andin vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.     

Synthesis of new salicylamide derivatives with evaluation of their antiinflammatory, analgesic and antipyretic activities

A new series of pyridazine, pyrazoles, pyrazolidine-3,5-dione, Semicarbazide, thiosemicarbazides, hydantoin, thiohydantoins, 1,2,4-triazoles, S-triazolo[3,4-b]-1,3,4-thiadiazoles incorporated indirectly into salicylamide moiety at position 2 were synthesized. Also the synthesis of novel series of 3-salicylamido-2-hydroxypropyl-amine derivatives were prepared. Several of these compounds were screened for antiinflammatory, analgesic, antipyretic and ulcerogenic activities.     

青藤碱衍生物的合成及其抗炎镇痛活性青藤碱衍生物的合成及其抗炎镇痛活性

目的为定向设计合成高效低毒的新一代青藤碱类药物提供线索。方法以青藤碱为先导物,对C环进行结构改造。结果共合成7个衍生物,进行了抗炎镇痛活性的筛选,结果表明,化合物2和5具有较好的抗炎镇痛作用。结论C环结构修饰值得进一步研究。     

Synthesis of novel benzimidazole derivatives: as potent analgesic agent

1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols have been synthesized using o-phenylinediamine and naphthaldehyde in the presence of sodium hydride and THF. 1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols were evaluated for the analgesic activity by tail flick method in rats. Synthesized1-(1-alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols in doses of 50 mg/kg increased the pain threshold significantly after 0, 30, 60, 90, and 120 min of administration in the tail flick model. Compounds B₃a, B₂b, and B₁b showed time-dependent action in all the experimental models. The present study indicates that Compounds B₃a, B₂b, and B₁b show analgesic properties.     

α-沉香呋喃衍生物的合成及中枢神经系统活性

目的 以沉香精油成分α-沉香呋喃为先导化合物，寻找具有神经系统作用的新化合物。方法从天然(-)香芹酮出发，经7步反应设计合成目标化合物，并经光谱方法确证结构。用4种小鼠行为学药理模型对目标物进行了活性测定。结果 合成了12个4位取代的α-沉香呋喃衍生物，其中10个为新化合物。药理试验结果表明：部分该类化合物具有抗焦虑作用和轻度的中枢神经抑制作用。结论 4位烷基碳为4-6个时，抗焦虑作用和中枢镇静、催眠作用明显，其抗焦虑的有效剂量为0．5-2mg／kg，小于中枢镇静、催眠的有效剂量5-20mg／kg。     

Synthesis and evaluation of nitrostyrene derivative compounds, new snake venom phospholipase A2 inhibitors

Several nitrostyrene derivatives were synthesized and their inhibitive activities on phospholipase A(2) (PLA(2)) from Bothrops jararacussu venom were evaluated. Some compounds were very efficient as inhibition agents against edema-inducing, enzymatic and myotoxic activities. Data revealed that the size of the substitute and substitution position in the nitrostyrene moiety had important influence on the inhibition capacities. The enzymatic kinetic studies show that the nitrostyrene derivatives compounds inhibit PLA(2) in a non-competitive manner. The electronic, molecular and topologic parameters were calculated using ab initio quantum calculations (density functional theory-DFT) and analyzed by chemometric methods (principal component analysis (PCA) and hierarchical cluster analysis (HCA)) in order to build models able to establish relationships between the electronic features and the structure-activity presented by the target compound. Compounds with the nitro group in the ortho, meta and para position (compounds 2-4) on the aromatic ring were more efficient in the inhibition of PLA(2) activity in all tests. These results indicate that the influence of the nitro group in the aromatic ring is, in fact, important. In addition, quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA(2) present lower values of highest occupied molecular orbital (HOMO) energy and polarizability, suggesting the formation of a charge-transferring complex between the nitrostyrene compounds and PLA(2).     

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 evaluation of DPPH and anti-inflammatory activities of 2,6-bisbenzylidenecyclohexanone and pyrazoline derivatives

A series of thirty three 2,6-bisbenzylidenecyclohexanone and pyrazoline derivatives were synthesized and evaluated for inhibitory activities on IFN-γ/LPS-activated RAW 264.7 cells and DPPH radical scavenging activity. Compounds 8, 9, and 11a demonstrated significant NO inhibitory activity as compared to L-NAME and curcumin with IC₅₀ values of 6.68 ± 0.16, 6.09 ± 0.46, and 6.84 ± 0.12 μM, respectively. Apparently the suppression upon NO secretion was not due to cell death since the active compounds did not reduce the cell viability in close proximity to the IC₅₀ of NO inhibition. Overall, incorporation of pyrazoline ring as part of the linker chain improved cell viability compared to the 2,6-bisbenzylidenecyclohexanone derivatives. Meanwhile, compound 11 (IC₅₀ = 13.27 ± 1.78 μM) bearing ortho hydroxyls on the aromatic rings recorded the highest radical scavenging activity as compared with quercetin (IC₅₀ = 21.46 ± 0.85 μM).     

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。     

Synthesis and anti-inflammatory and analgesic activities of phenoxyalkanoic acid derivatives

The synthesis of phenoxyalkanoic acid derivatives and their anti-inflammatory and analgesic activities are described. Analysis of structure-activity relationships shows that in trichlorophenoxy derivatives anti-edematous potency is associated with the presence of 1-thiopropyl moiety and 2 or 4-aminopyridyl moiety at R′ position contributes to the analgesic activity.     

Synthesis of new imidazolyl acetic acid derivatives with anti-inflammatory and analgesic activities

We synthesized 2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl) 5-oxo-4,5-dihydroimidazol-1-yl) acetic acid 3. Chlorination afforded the chloro derivative 4, which reacted with different amines and hydrazine to afford compounds 5–8. Pyrazole, pyrazolone, and thiazolidinone derivatives were also synthesized from Imidazol-1-ylacetic acid hydrazide 8 to give compounds 9–12. Compounds were then evaluated for their anti-inflammatory activity against carrageenan-induced rat paw edema and their analgesic activity using the writhing test in albino mice. Compounds 5, 9, 10, 12 exhibited maximum anti-inflammatory activity, and all the compounds inhibited writhing, with 10 and 12 being two times more effective than the reference standard.     

Synthesis and analgesic and anti-inflammatory activities of 1,2-benzothiazine derivatives

Three 1,2-benzothiazine derivatives were synthesized, and their analgesic/anti-inflammatory efficacy and their effects on gastric irritation were evaluated. Among the three compounds, 39 exhibited the most potent analgesic action, but the effect was weaker than that of piroxicam. Nonetheless, the compound showed 4 times more potent analgesic action with less gastric damage than did ibuprofen. These compounds did not show anti-inflammatory effect at an oral dose of 5 mg/kg.     

Potential analgesic and anti-inflammatory activities of Panax ginseng head butanolic fraction in animals

The present study reports the potential anti-rheumatoid activity of Panax ginseng head part. P. ginseng-head part BuOH fraction (PGHB) was safe in acute toxicity (LD₅₀ > 5000 mg/kg) and inhibited the partially acetic acid-induced writhes (approximately 32%, P < 0.05) in mice. PGHB (500 mg/kg) inhibited the acetic acid-induced extravasation of Evan’s blue dye in mice by approximately 20.6% (P < 0.05), and was similar to the suppressive effect of ibuprofen (27.7%) as a positive control drug. Also, PGHB reduced the carrageenan-induced paw edema at 3 h after oral administration, and suppressed the production of serum IL-6 in CIA mice. This suggests that PGHB has potential analgesic and anti-inflammatory activities, and will be the supporting evidence for the potential anti-rheumatoid activity of Korean P. ginseng-head.     

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.