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1.
Syntheses of natural homoisoflavonoids, (±)-portulacanones A–C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10?μM; IC50?=?1.26?µM) followed by 6 (portulacanone D) (92.5% at 10?μM; IC50?=?2.09?µM), 1 (91.4% at 10?μM; IC50?=?1.75?µM) and 7 (83.0% at 10?μM; IC50?=?2.91?µM) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases.  相似文献   

2.
Novel derivatives of flurbiprofen 118 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 29, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 1115, and benzyl substituted 2-mercapto oxadiazole derivatives 1618 were synthesized and characterized by EI-MS, 1H and 13C NMR spectroscopic techniques. All derivatives 118 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC50 = 1.04 ± 0.3 to 2.41 ± 0.09 µM as compared to the standard acarbose (IC50 = 0.9 ± 0.04 µM). Out of eighteen compounds, derivatives 2 (IC50 = 1.69 ± 0.1 µM), 3 (IC50 = 1.04 ± 0.3 µM), 9 (IC50 = 1.25 ± 1.05 µM), and 13 (IC50 = 1.6 ± 0.18 µM) found to be excellent inhibitors while rest of the compounds demonstrated comparable inhibition potential. A limited structure-activity relationship (SAR) was established by looking at the varying structural features of the library. In addition to that, in silico study was conducted to understand the binding interactions of the compounds (ligands) with the active site of α-amylase enzyme.  相似文献   

3.
Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC50 values of 5.2?±?0.6, 3.4?±?0.4, and 6.7?±?0.8?µM against the drug-resistant Dd2 strain of Plasmodium falciparum. In addition the prenylated stilbene 5 also showed good activity, with IC50 5.8?±?0.7?µM.  相似文献   

4.
A novel triazole derivatives(±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one (12a–j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. β-Amino alcohol derivatives of 1-indanone (15a–l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC50: 1.388024 µM), 12g (IC50: 1.220696 µM), 12j (IC50: 1.312428 µM) and 15k (IC50: 1.349671 µM) and 15l (IC50: 1.330764 µM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril.  相似文献   

5.
Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93?±?0.29?µM for Plm II; Ki, 1.99?±?0.05?µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84?±?0.08?µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27?±?0.95?µM for 10f; IC50, 3.11?±?0.65?µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35?±?0.85?µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.  相似文献   

6.
Eight new C21 steroidal glycosides, namely cynanotins A–H (18), together with fifteen known analogues, were isolated from the roots of Cynanchum otophyllum. Their structures were elucidated by spectroscopic analysis and chemical methods. In this study, all of isolates were tested for their vitro inhibitory activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Compounds 315 showed moderate cytotoxic activities against HL-60 cell lines with IC50 values ranging from 11.4 to 37.9?µM. Compounds 5, 9, and 10 showed marked or moderate cytotoxic activities against five human tumor cell lines with IC50 values ranging from 11.4 to 36.7?µM. Compound 11 displayed moderate cytotoxic activities against HL-60, SMMC-7721, MCF-7 and SW480 cell lines with IC50 values of 12.2–30.8?µM. Compared to the positive control (IC50: 35.0?µM), compounds 5, 911 exhibited more potential inhibitory activity against MCF-7 cells (IC50: 16.1–25.6?µM).  相似文献   

7.
Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (112) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC50s of (2.4–52.5?µM), and α-glucosidase with IC50 values of (1.7–72.7?µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50?=?2.4?µM for 3, 2.8?µM for 7) and α-glucosidase (IC50?=?4.8?µM for 3, 1.7?µM for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of α-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: Kiapp?=?2.4?µM; k5?=?0.05001?µM?1?S?1 and k6?=?0.02076?µM?1?S?1.  相似文献   

8.
Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (125) were synthesized and evaluated for their α-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC50 values between 22.1 ± 0.9 and 136.2 ± 5.7 μM, when compared with standard acarbose (IC50 = 840 ± 1.73 μM). The most potent compounds 4, 9, and 10 showed IC50 values in the range of 22.1 ± 0.9 to 25.6 ± 1.5 μM. Compounds 2, 5, 11, and 19 showed IC50 values within the range of 40.2 ± 0.5 to 60.9 ± 2.0 μM. Compounds 1 and 3 were also found to be good inhibitors with IC50 values 136.2 ± 5.7 and 104.8 ± 9.9 μM, respectively. Their activities were compared with α-glucosidase inhibitor drug acarbose (standard) (IC50 = 840 ± 1.73 μM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of α-glucosidase enzyme. All the active compounds (15, 911, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC50 = 0.80 ± 0.12 μM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies.  相似文献   

9.
A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50?=?0.29?±?0.01?μM and 0.46?±?0.02?μM, respectively), MAO-A (IC50?=?8.2?±?0.08?μM and 7.9?±?0.07?μM, respectively) and MAO-B (IC50?=?20.1?±?0.16?μM and 43.8?±?2.0% at 10?μM, respectively) inhibitory activities, moderate self-induced Aβ1–42 aggregation inhibitory potency (35.4?±?0.42% and 48.0?±?1.53% at 25?μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.  相似文献   

10.
Four new aromatic meroterpenoids, ganocapenoids A–D (14), together with twelve known analogues (516) were isolated from the fruiting bodies of Ganoderma capense. The structures of new compounds were determined through spectroscopic methods including 1D and 2D NMR and MS analyses. Their absolute configurations were assigned by ECD calculations and specific rotation comparison. The biological activities of these substances toward regulation of lipid metabolism, neurite outgrowth-promoting activity, and AchE inhibition were assessed. Compound 15 was found to be able to block lipid accumulation at a concentration of 20?μM, and compounds 4a, 4b, and 11 show moderate neurite outgrowth-promoting activity at 10?μM, while compounds 3, 6, 11, and 13 exhibit potent AchE inhibition with the IC50 values of 28.6?±?1.9, 18.7?±?1.6, 8.2?±?0.2, 26.0?±?2.9?μM, respectively.  相似文献   

11.
Benzohydrazide derivatives 143 were synthesized via “one-pot” reaction and structural characterization of these synthetic derivatives was carried out by different spectroscopic techniques such as 1H NMR and EI-MS. The synthetic molecules were evaluated for their in vitro urease inhibitory activity. All synthetic derivatives showed good inhibitory activities in the range of (IC50 = 0.87 ± 0.31–19.0 ± 0.25 µM) as compared to the standard thiourea (IC50 = 21.25 ± 0.15 µM), except seven compounds 17, 18, 23, 24, 29, 30, and 41 which were found to be inactive. The most active compound of the series was compound 36 (IC50 = 0.87 ± 0.31 μM) having two chloro groups at meta positions of ring A and methoxy group at para position of ring B. The structure–activity relationship (SAR) of the active compounds was established on the basis of different substituents and their positions in the molecules. Kinetic studies of the active compounds revealed that compounds can inhibit enzyme via competitive and noncompetitive modes. In silico study was also performed to understand the binding interactions of the molecules (ligand) with the active site of enzyme.  相似文献   

12.
A series of benzamide derivatives 112 with various functional groups (–H, –Br, –F, –OCH3, –OC2H5, and –NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure–activity relationship showed that the substitution of –Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 112 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 34, and 78 showed a mixed mode of inhibition against BCHE, while compounds 2, 56 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others.  相似文献   

13.
derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC50 values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC50 values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC50 value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC50 = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC50 = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.  相似文献   

14.
Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g) was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC50 = 0.87–3.78 µM), in particular, the derivatives 9e (IC50 = 0.92 µM), 9g (IC50 = 0.87 µM) and 9k (IC50 = 1.02 µM) recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC50 = 1.11 µM). The in vivo potent compounds (9e, 9g and 9k) caused variable ulceration effect (ulcer index = 5–12.25) in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k) to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.  相似文献   

15.
Chagas disease and leishmaniasis are tropical neglected diseases caused by kinetoplastids protozoan parasites of Trypanosoma and Leishmania genera, and a public health burden with high morbidity and mortality rates in developing countries. Among difficulties with their epidemiological control, a major problem is their limited and toxic treatments to attend the affected populations; therefore, new therapies are needed in order to find new active molecules. In this work, sixteen Laurencia oxasqualenoid metabolites, natural compounds 111 and semisynthetic derivatives 1216, were tested against Leishmania amazonensis, Leishmania donovani and Trypanosoma cruzi. The results obtained point out that eight substances possess potent activities, with IC50 values in the range of 5.40–46.45 µM. The antikinetoplastid action mode of the main metabolite dehydrothyrsiferol (1) was developed, also supported by AFM images.The semi-synthetic active compound 28-iodosaiyacenol B (15) showed an IC50 5.40 µM against Leishmania amazonensis, turned to be non-toxic against the murine macrophage cell line J774A.1 (CC50 > 100). These values are comparable with the reference compound miltefosine IC50 6.48 ± 0.24 and CC50 72.19 ± 3.06 μM, suggesting that this substance could be scaffold for development of new antikinetoplastid drugs.  相似文献   

16.
Current study deals with the evaluation of indane-1,3-dione based compounds as new class of urease inhibitors. For that purpose, benzylidine indane-1,3-diones (130) were synthesized and fully characterized by different spectroscopic techniques including EI-MS, HREI-MS, 1H, and 13C NMR. All synthetic molecules 130 were evaluated for urease inhibitory activity and showed good to moderate inhibitory potential within the range of (IC50 = 11.60 ± 0.3–257.05 ± 0.7 µM) as compared to the standard acetohydroxamic acid (IC50 = 27.0 ± 0.5 µM). Compound 1 (IC50 = 11.60 ± 0.3 µM) was found to be most potent inhibitor amongst all derivatives. The key binding interactions of most active compounds within the enzyme pocket were evaluated through in silico studies.  相似文献   

17.
Two new glycoalkaloids, erianosides A (1) and B (2) along with five known compounds (37) were isolated from the leaves of Solanum erianthum. Their structures were elucidated from analyses of spectroscopic data and all isolates were tested for in vitro cytotoxic activity against human breast cancer cell lines (BT-549, MDA-MB-231, T74D, and MCF-7). Solasonine (5) and solamargine (6) were active against the aforementioned four cancer cell lines with IC50 values of 27.26–35.89 and 5.84–10.13 μM, respectively. Erianoside A (1) (T74D: IC50, 56.39 µM) and solasodine (3) (BT-549 and MDA-MB-231: IC50, 59.15 and 75.63 µM, respectively) had moderate cytotoxic effects towards some cell lines in the panel.  相似文献   

18.
Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (14) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 13 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC50 of 20 and 32?µM respectively and against PC-3 with an IC50 of 14 and 18?µM respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC50 of 10.3?µM using ascorbic acid as a positive control.  相似文献   

19.
A new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC50 = 1.55 ± 0.07–2.65 ± 0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC50 = 15.08 ± 0.71 µg/mL) and acetohydroxamic acid (IC50 = 21.05 ± 0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC50 value of 1.55 ± 0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.  相似文献   

20.
Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC50 values between 0.4 and 1.0 µM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC50 = 0.7 μM). Compound 7h demonstrated the best antileishmanial activity with an IC50 value of 0.4 µM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC50s below 2.0 μM and SI between 2.7 and 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC50s in the range of 1.1–2.7 µM and SI values between 1.1 and 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC50 value of 1.9 µM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.  相似文献   

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