Potent in vitro and in vivo antitubercular activity of certain newly synthesized indophenazine 1,3,5-trisubstituted pyrazoline derivatives bearing benzofuran

Fourteen newly synthesized derivatives of indophenazine 1,3,5-trisubstituted pyrazoline bearing benzofuran were prepared from benzofuran chalcones with indophenazine hydrazide through cycloaddition reaction. All the compounds were screened for their in vitro and in vivo antitubercular activity against drug resistant and multidrug-resistant Mycobacterium tuberculosis H₃₇RV. The MIC₅₀ and MIC₉₀ were estimated and compared with rifampicin and gatifloxacin standard drugs. Nitro group containing at ortho 5j, meta 5e, furan ring containing 5m and ortho 5i, para 5h chloro containing compounds were exhibited significant in vitro, in vivo antitubercular activity against standard drugs.     

Biological evaluation of novel 1,4-dithiine derivatives as potential antimicrobial agents

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.     

Antibacteriophage Properties of Some Greek Plant Extracts

Abstract

The ethanol extracts (70%) of 45 plants grown in Greece were screened for antibacteriophage properties against 6 bacteriophages: coliphages T₁, T₂, T₄, T₇, φX174, and MS₂- Eight samples were found to induce a significant antiphage activity and can be used as material for further antiviral studies in vitro and in vivo.     

Aryloxyacetic esters structurally related to α-Asarone as potential antifungal agents

Abstract  

A series of aryloxyacetic ester analogues 8–13 was synthesized based on the potential pharmacophores of the antifungal agents α-Asarone (1) and 2–5. Their antifungal activity was tested in vitro for their growth inhibitory activities against pathogenic fungi. The in vitro antifungal evaluation of these alkyl and aryl esters shows that derivatives 10 displayed the highest antifungal and fungicidal activities against Cryptococcus neoformans and C. gattii. These results support the idea that the phenoxyacetic frame is a potent pharmacophore for the design of potential antifungal drugs.     

In vitro characterization,ADME analysis,and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains

BackgroundCandida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.ObjectiveA compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.MethodsIn vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.ResultsThe current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.ConclusionsThe results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.     

Synthesis of novel Hantzsch dihydropyridines and Biginelli dihydropyrimidines of biological interest: a 3D-QSAR study on their cytotoxicity

We report a library consisting of some novel Hantzsch dihydropyridines and Biginelli dihydropyrimidines of biological interest as well as their synthesis and analysis. The important steps in the synthetic part were found to be Hantzsch and Biginelli multicomponent reactions. The synthesized compounds were screened for their in vitro antibacterial activity against two gram-positive bacteria: Staphylococcus aureus and Bacillus subtilis. The title compounds did not exhibit potential antibacterial activity. Furthermore, compounds were subjected to in vitro cytotoxicity against Vero cells. Compounds exhibited weak, moderate, or high cytotoxicity. Compounds 4a, 4b, 4c, 4f, 4g, 4h, 4i, 7i, 7l, 7m, and 7r exhibited potential cytotoxicity. CoMFA study has resulted in the identification of structural features contributing toward their cytotoxicity.     

A Structured–Activity Relationship Study of Batracylin Analogues

A number of isoindolo[l ,2-b]quinazolines and some benzo[4,5]isoquinolino[l,2-b]quinazolines as structural modification analogues of the antitumor compound batracylin were synthesized and evaluated against HL-60 cell growth and in topoisomerase II-mediated DNA cleavage assays. Of the compounds studied, 10,12-dihydro-7,8-methy lenedioxyisoindolo[ 1,2-b] quinazolin-12(10H)-one (1d), 2-amino-10,12-dihydroisoindolo[l ,2-b]quinazolin- 12(10H)-one (1p), and 2-amino-7,8-methylenedioxy-10,12-dihydroisoindolo[l ,2-b]quinazolin-12(10H)-one (1ab) exhibited good inhibitory activities against HL-60 cell lines as well as induction of topo II-mediated DNA cleavage activities.     

Effect of anhydrosophoradiol-3-acetate of Calotropis gigantea (Linn.) flower as antitumoric agent against Ehrlich's ascites carcinoma in mice

BackgroundOver 60% of currently used anti-cancer agents are derived in one-way or another from natural sources, including plants, marine organisms and microorganisms. Calotropis gigantea (Linn.) (Family: Asclepiadaceae) is a perennial shrub and it is used as a traditional folk medicine for the treatment of various health complications. But there is no report on isolation of anticancerous chemicals from the flower of Calotropis gigantea. The objective of the present study is to explore the antitumor effect of anhydrosophoradiol-3-acetate (A3A), isolated from the flower of Calotropis gigantea (Linn.) against Ehrlich's ascites carcinoma (EAC) in Swiss albino mice.MethodsAntitumoric effect of A3A was assessed by evaluating viable tumor cell count, survival time, body weight gain due to tumor burden, hematological and biochemical (glucose, cholesterol, triglyceride, blood urea, SALP, SGPT and SGOT) parameters of EAC bearing host at doses of 10 and 20 mg/kg body weight.ResultsTreatment with A3 A decreased the viable tumor cells and body weight gain thereby increasing the life span of EAC bearing mice. A3A also brought back the altered hematological (Hb, total RBC and total WBC) and biochemical parameters more or less to normal level.ConclusionResults of this study conclude that in vivo the A3A was effective in inhibiting the growth of EAC with improving in cancer induced complications.     

Sphingolipid Analogues Inhibit Development of Malaria Parasites

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Delivery of amphotericin B nanosuspensions to the brain and determination of activity against Balamuthia mandrillaris amebas

Amphotericin B was formulated as nanosuspensions to develop a nanoparticulate brain delivery system. Nanosuspensions were produced with different surfactant solutions by high-pressure homogenization and then characterized by laser diffractometry and photon correlation spectroscopy. Before in vitro and in vivo testing all nanosuspensions were investigated for protein adsorption by two-dimensional polyacrylamide gel electrophoresis to predict brain-targeting capacities. Selected nanosuspensions were tested for amebicidal activity against Balamuthia mandrillaris, an agent of lethal encephalitis. Our results indicate that nanosuspensions coated with polysorbate 80 and sodium cholate markedly increased drug brain delivery and inhibited the parasite in vitro, though less in vivo.From the Clinical EditorThe antifungal Amphotericin B was formulated as nanosuspensions to develop a nanoparticulate brain delivery system. The results indicate that nanosuspensions coated with polysorbate 80 and sodium cholate markedly increased drug brain delivery and inhibited the parasite in vitro, though less in vivo.     

含丙基侧链的新型三唑类化合物的设计、合成和抗真菌活性研究

目的 研究具有正丙基侧链和二取代苯环结构的三唑醇类化合物的抗真菌活性。方法 设计合成了11个目标化合物;其结构通过¹H NMR确证,部分化合物还通过¹³C NMR、高分辨质谱(HRMS)确证;选择3种真菌为实验菌株,根据美国国家临床实验室标准委员会(NCCLS)推荐的标准化抗真菌敏感性实验方法,进行体外抑菌活性测试。结果 化合物B11对白念珠菌SC5314的活性较氟康唑更好,与泊沙康唑相当;化合物B10、B11、B4对新型隐球菌H99的活性较氟康唑更好,化合物B2、B3、B5、B6、B7对新型隐球菌H99的活性与氟康唑相当;所有化合物对烟曲霉菌活性欠佳。结论 部分引入正丙基侧链和二取代苯基结构的目标化合物有一定抗真菌活性,可作为潜在的先导抗真菌药物。     

牛樟芝水提取物抗过敏作用及其机制研究

目的 研究牛樟芝水提物的抗过敏作用并初步探讨其作用机制。方法 采用大鼠被动皮肤过敏模型、小鼠迟发型超敏模型、小鼠全身皮肤瘙痒模型、小鼠腹腔毛细血管通透性模型,观察牛樟芝水提物在体抗过敏作用。采用体外培养的RBL-2H3肥大细胞,观察牛樟芝水提物对细胞增殖及凋亡的影响,初步探讨其抗过敏反应的作用机制。结果 体内试验中,牛樟芝水提物显著降低大鼠被动皮肤过敏反应,明显降低小鼠耳肿胀度、胸腺指数及脾指数,提高右旋糖酐所致皮肤瘙痒阈值,减少小鼠瘙痒次数,抑制组胺所致血管通透性上升;体外试验中,其剂量相关性的抑制RBL-2H3细胞增殖,促进细胞凋亡。结论 牛樟芝水提取物有一定的抗过敏作用,其机制与促进RBL-2H3细胞凋亡有关。     

Synthesis and Structure-Activity Relationships of Vasicine Analogues as Bronchodilatory Agents

The series of vasicine (1) analogues, an alkaloid from Adhatoda vasica Nees., were synthesized with changes in A, B or C rings. Compounds 13-19 were evaluated for in vitro bronchodilatory activity using isolated guinea pig tracheal chain. Compounds 3-8 were also synthesized in good yields using microwave-mediated synthesis under solvent free conditions. Compounds 5 and 8 with seven-member C ring were more active than etofylline and caused 100% relaxation of both the histamine and acetycholine pre-contracted guinea pig tracheal chain. The structure-activity relationship studies showed that the quinazoline and oxo functionalities were essential for activity. The compounds without C ring and instead having aliphatic and phenyl substitutions in B ring showed relaxation against histamine pre-contracted tracheal chain only, 2-methyl substituted analogues, 12 and 13, being most active with 100% relaxation effect.     

Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives

Gatifloxacin is a synthetic broad-spectrum fluorquinolone antibacterial agent with a 3-methylpiperazinyl-side chain at position 7 and a methoxy group at position 8 of the quinolone ring. In the present study different analogues of gatifloxacin were prepared; the piperazinyl ring was chosen as the center of reaction for synthesizing this series of derivatives. The structures of these derivatives were established using spectroscopic techniques such as IR, ¹H NMR, and EIMS. In vitro antibacterial and antifungal activities were evaluated by disc diffusion method and these derivatives were compared with in-use fluoroquinolones like gatifloxacin, sparfloxacin, and gemifloxacin. Derivative A proved very potent against Gram-negative organisms, especially Pseudomonas aeruginosa, Shigella flexeneri, and Klebseilla pneumoniae, and derivatives A–C exhibited good antifungal activity compared to in-use quinolones. In addition, gatifloxacin and derivatives were investigated for immunomodulating activities. Derivative B has good anti-inflammatory activity, with IC₅₀ < 12.5 μg/ml.     

Synthesis, cytostatic and anti-viral activity evaluation of the novel acyclic nucleoside analogues containing a sterically constrained (Z)-4-amino-2-butenyl moiety

A series of the novel pyrimidine (3–6) and purine (12–15, 18–21) acyclic nucleoside analogues in which the sugar moiety was replaced by a sterically constrained Z-4-amino-, 4-aminohydrochloride-2-butenyl, or aliphatic 4-aminohydrochloride-2-butyl moiety were synthesized and evaluated for their anti-viral and cytostatic activity potency. Cytostatic evaluation of the novel compounds on selected panel of human tumour-cell lines showed that the majority of compounds exerted a non-specific anti-proliferative effect at the highest tested concentration (i.e. 1 × 10⁻⁴ M) against all cell lines. Nevertheless, a rather moderate but selective anti-proliferative effects on HeLa cell cultures in comparison to normal fibroblasts WI 38, were observed for compounds 15 and 21. No anti-viral activity was observed, except for compounds 3, 4, 5 and 19 that showed anti-HIV activity at 50% effective concentration ranging between 10 and 96 μM.     

Ameliorative effects of vitamin B17 on the kidney against Ehrlich ascites carcinoma induced renal toxicity in mice

Cancer is the major cause of death and many factors that lead to its occurrences, such as environmental pollution and pesticides and other factors. Ehrlich carcinoma development depends on many things associated with the environment, nutrition, personal habits, and family history. The present study aimed to evaluate the potential protective effects of vitamin B17 (VB17) against Ehrlich ascites carcinoma (EAC) that induced kidney toxicity in female mice. The mice were divided into five groups (first group, control group; second group, VB17 group; third group, EAC group; fourth group, pretreated EAC with VB17; fifth group, cotreated EAC with VB17). Results showed the VB17 in pretreated (G4) and cotreated (G5) groups lead to an improvement in DNA damage and cytological examination, in addition significantly (P < .05) increase in Na⁺, red blood cell, hemoglobin, hematocrit value, mean corpuscular hemoglobin (MCH), and MCH concentration, whereas significantly (P < .05) decrease in urea, creatinine, K⁺, platelets, and white blood cells while insignificant (P < .05) changes in mean corpuscular volume when compared to the EAC group. Many histopathological changes were observed in kidney sections in EAC as marked damage and degenerated, glomerular atrophy, the Malpighian corpuscles that lost their characteristic configuration. On the other hand, a moderate improvement and arrangement in the kidney histological structure in pretreated VB17 + EAC, while a mild enhancement and arrangement of the kidney structure in cotreated EAC + VB17. In addition, depletion in renal P53 and PCNA protein expression compared with the EAC group. It could be concluded that VB17 has a potential renal protective effect against EAC cells induced kidney injury.     

Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations

Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.     

Antiangiogenic and growth inhibitory effects of synthetic novel 1, 5-diphenyl-1,4 pentadiene-3-one-3-yl-ethanone pyridine curcumin analogues on Ehrlich ascites tumor in vivo

In the present investigation we have synthesized novel substituted dienone pyridine ethanone curcumin analogues 3a and 3b by nucleophilic substitution reactions with 2-bromo-1-pyridine-3-yl ethanone and characterized by ¹H nuclear magnetic resonance (NMR), infrared IR, mass, and CHNS analysis. The compounds demonstrated tumor growth inhibition and antiangiogenic effects against mouse Ehrlich ascites tumor in vivo and suppressed neovascularization in a chorio allantoic membrane model.     

Synthesis,antimicrobial evaluation,and QSAR analysis of 2-isopropyl-5-methylcyclohexanol derivatives

A series of 2-isopropyl-5-methylcyclohexanol derivatives were synthesized and evaluated for their antibacterial activity against Gram-positive Staphylococcus aureus and Bacillus subtilis and Gram-negative Escherichia coli and in vitro antifungal activity against Candida albicans and Aspergillus niger. The results of antimicrobial activity demonstrated that the compounds 10, 20, and 21 were the most active ones among the synthesized compounds. The QSAR studies revealed the importance of dipole moment (μ), total energy (Te), and topological parameters (κ₁ and κ₃) in describing the antimicrobial activity of 2-isopropyl-5-methylcyclohexanol derivatives.     

12-Amino-andrographolide analogues: synthesis and cytotoxic activity

Andrographolide, a diterpenoid lactone of the plant Andrographis paniculata, has been shown to be cytotoxic against various cancer cells in vitro. In the present study, a series of β-amino-γ-butyrolactone analogues has been synthesized from naturally occurring andrographolide via one pot tandem aza-conjugate addition–elimination reaction. By using economic procedure without any base or catalyst at room temperature, the products obtained were in fair to excellent yields with high stereoselectivity. The cytotoxicity of all new amino analogues were evaluated against six cancer cell lines and revealed their potential for being developed as promising anti-cancer agents.