Synthesis,characterization of 4,6-disubstituted aminopyrimidines and their sulphonamide derivatives as anti-amoebic agents

The present study describes the synthesis and anti-amoebic activity of 4,6-disubstituted aminopyrimidines (1b–10b) and their sulphonamide derivatives (1–20). All the desired compounds were characterized by spectral data and their purity was confirmed by elemental analysis. The aim of the study was to explore the effect of the target compounds on in vitro growth of HM1:IMSS strain of Entamoeba histolytica. In vitro anti-amoebic activity was performed by microdilution method and the results were compared with standard drug metronidazole. The results revealed that sulphonamide derivatives (1–20) showed better activity than 4,6-disubstituted aminopyrimidines (1b–10b). 5 pyrimidine and 12 sulphonamide derivatives were better inhibitors of the growth of E. histolytica than the reference drug metronidazole (IC₅₀ = 1.80 μM). The promising in vitro anti-amoebic activity of the compounds make them promising molecules for further lead optimization in the development of novel anti-amoebic agents, therefore, it is hoped that these preliminary results could help in designing better molecules with an enhanced anti-amoebic activity.     

Synthesis of indole-2-hydrazones in search of potential leishmanicidal agents

Indole-2-hydrazones 3–30 were synthesized and evaluated for their antileishmanial activity. The compounds 24 (IC₅₀ = 1.86 ± 0.09 μM), 12 (IC₅₀ = 2.26 ± 0.16 μM), 23 (IC₅₀ = 3.81 ± 0.29 μM), 8 (IC₅₀ = 4.01 ± 0.32 μM), 17 (IC₅₀ = 4.89 ± 0.31 μM), 20 (IC₅₀ = 4.89 ± 0.26 μM), 3 (IC₅₀ = 5.12 ± 0.34 μM), 15 (IC₅₀ = 5.26 ± 0.26 μM), 6 (IC₅₀ = 6.16 ± 0.38 μM), and 21 (IC₅₀ = 6.18 ± 0.045 μM) showed better activities than standard pentamidine (IC₅₀ = 7.02 ± 0. 09 μM). Compounds 4, 5, 7, 9–11, 13, 16, 18, 19, 22, 25–28, and 30 displayed good activities. The compounds 14 and 29 were found to be inactive. The synthesized compounds were characterized by different spectroscopic techniques.     

Pyrazolo[3,4-d]pyrimidine analogues: synthesis, characterization and their in vitro antiamoebic activity

Pyrazolo[3,4-d]pyrimidine analogues were synthesized by treating 3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine with different sulfonyl chlorides and triethylamine in dry dichloromethane. The structure of all the compounds was elucidated by spectral data and their purity was confirmed by elemental analysis. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica and two compounds, 4 (IC₅₀ = 0.57) and 6 (IC₅₀ = 0.68), were found better inhibitors than the reference drug metronidazole (IC₅₀ = 1.80). Further, both the compounds (4 and 6) were low cytotoxic against the human breast cancer MCF-7 cell line in the concentration range of 2.5–250 μM. These preliminary results reveal that pyrazolo[3,4-d]pyrimidine analogues could help in designing better molecules with enhanced antiamoebic activity.     

Synthesis, molecular modeling, and biological evaluation of 1,2,4-triazole derivatives containing pyridine as potential anti-tumor agents

There is an accumulating body of experimental evidences validating focal adhesion kinase (FAK) as a therapeutic target and offering opportunities for anti-tumor drug development. In present study, we sought to synthesize twenty-eight potential FAK inhibitors as anti-tumor agents based on 1,2,4-triazole skeleton. The bioassay assays demonstrated that compounds 3e and 6j showed the most potent activity, 3e inhibited the growth of HCT116 and HepG2 cell lines with IC₅₀ values of 8.17 and 7.04 μM, while compound 6j showed the most potent biological activity against HCT116 cell line (IC₅₀ = 1.99 μM). Besides, compound 6j also exhibited significant FAK inhibitory activity (IC₅₀ = 2.41 μM). The results of flow cytometry and western-blot assay demonstrated that compounds 3e and 6j possessed good anti-proliferative activity. Docking simulations were performed to position compounds 3e and 6j into the active site of FAK to determine the probable binding model.     

Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives

A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC₁₆ = 0.7 μM) and 31 (IC₁₆ = 1.7 μM) and 33 (IC₁₆ = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C₁₁-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents.     

Synthesis,molecular docking studies,and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors

On the basis of observed biological activity of barbiturates/thiobarbiturates, a set of 13 hydrazinecarboxamide/hydrazinecarbothioamides derivatives were designed and synthesized in good to excellent yield with extensive structural characterization. These compounds were screened for antibacterial and cholinesterase inhibitory activities. Two of the compounds 1 and 2 showed moderate bactericidal activity. Compounds 10 and 4 were found to be the most active acetyl/butyryl cholinesterase inhibitor, respectively (AChEI; 10; IC₅₀ = 40.78 μM and BChEI; 4; IC₅₀ = 3.31 μM). In silico molecular docking studies were carried out to identify active interacting sites of drug and enzyme and to establish structure–activity relationships. When predicted cholinesterase binding energies were compared with the experimentally determined inhibitory concentrations (IC₅₀), most active compounds were also found to be the most favorable for binding. The binding scores of compounds 10 and 4 were ?10.2 and ?9.3 kcal/mol, respectively.     

2-(2′-Pyridyl) benzimidazole derivatives and their urease inhibitory activity

Pyridyl-benzimidazole analogues 1–11 with variable substituent on phenyl ring of phenacyl moiety were synthesized and evaluated for their urease inhibitory activity. The compounds exhibited urease inhibition with IC₅₀ between 19.22 and 77.31 µM. Compounds 4 (IC₅₀ = 19.22 ± 0.49 µM) showed a urease inhibition comparable to thiourea (IC₅₀ = 21.00 ± 0.01 µM) and twofold more active than acetohydroxamic acid (IC₅₀ = 42.00 ± 1.26 µM) (standards), respectively. Moreover, compounds 5 (IC₅₀ = 21.55 ± 0.36 µM), 1 (IC₅₀ = 24.37 ± 0.41 µM), 7 (IC₅₀ = 25.44 ± 0.19 µM), 6 (IC₅₀ = 27.62 ± 0.25 µM), 3 (IC₅₀ = 31.32 ± 0.75 µM), 8 (40.88 ± 0.36 µM) and 9 (41.22 ± 0.42 µM) also exhibited excellent activities when compared to the standards. Compounds 2 (IC₅₀ = 65.46 ± 0.75 µM), 10 (68.99 ± 0.33 µM) and 11 (77.31 ± 0.51 µM) showed a moderate activity. The size of the substituents and their electron donating or withdrawing affects as well as their position on phenyl apparently modulates the enzyme inhibitory activity.     

Synthesis,in vitro and in vivo giardicidal activity,and pharmacokinetic profile of a new nitazoxanide analog

4-Nitro-N-(5-nitro-1,3-thiazol-2-yl)benzamide (1), a new nitazoxanide analog, was synthesized; its chemical structure was confirmed by ¹H, ¹³C NMR, and HRMS. In this study, we evaluated the in vitro activity of compound 1 against Giardia lamblia trophozoites, as well as its in vivo giardicidal activity in a CD-1 mouse model. A pharmacokinetic study in Wistar rats evaluated compound 1 disposition after intravenous (IV) and oral administration of 3.3 and 150 mg/kg, respectively. Compound 1 inhibited G. lamblia growth in vitro with a median inhibitory concentration (IC₅₀) of 0.78 ± 0.01 μM, and thus was more effective than metronidazole (IC₅₀ = 5.36 ± 0.23 μM), the drug of choice against this parasite. An evaluation of cytotoxicity using VERO cells showed that compound 1 was less cytotoxic than metronidazole (CC₅₀ = 685.98 vs. CC₅₀ = 68 μM, respectively), with a favorable selectivity index (SI = 879). In vivo, we found that 97.2 % of parasite load was eliminated after intragastric administration of compound 1 (75 mg/kg). An analysis of the oral pharmacokinetic profile revealed a double peak of maximum concentration. Pharmacokinetic parameters indicated an absolute bioavailability approaching 33 %, a prolonged half-life, a large distribution volume, and slow clearance. This pharmacokinetic behavior of compound 1 makes it a promising candidate for the treatment of infections caused by both intestinal and systemic parasites.     

Acylated phenylethanoid glycosides,echinacoside and acteoside from Cistanche tubulosa,improve glucose tolerance in mice

Acylated phenylethanoid glycosides, echinacoside (1) and acteoside (2), principal constituents in stems of Cistanche tubulosa (Orobanchaceae), inhibited the increase in postprandial blood glucose levels in starch-loaded mice at doses of 250–500 mg/kg p.o. These compounds (1 and 2) also significantly improved glucose tolerance in starch-loaded mice after 2 weeks of continuous administration at doses of 125 and/or 250 mg/kg/day p.o. without producing significant changes in body weight or food intake. In addition, several constituents from C. tubulosa, including 1 (IC₅₀ = 3.1 μM), 2 (1.2 μM), isoacteoside (3, 4.6 μM), 2′-acetylacteoside (4, 0.071 μM), tubulosides A (5, 8.8 μM) and B (9, 4.0 μM), syringalide A 3-O-α-l-rhamnopyranoside (10, 1.1 μM), campneoside I (13, 0.53 μM), and kankanoside J₁ (14, 9.3 μM), demonstrated potent rat lens aldose reductase inhibitory activity. In particular, the potency of compound 4 was similar to that of epalrestat (0.072 μM), a clinical aldose reductase inhibitor.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

Synthesis, biological evaluation and molecular modeling studies of Schiff bases derived from 4-methylsalicylic acid as potential immunosuppressive agents

A series of Schiff bases derived from 4-methylsalicylic acid (4a–4s) were synthesized, 14 of which (4a–4h, 4j–4l, 4n, 4q, and 4s) were reported for the first time. All the synthesized compounds were evaluated for their immunosuppressive activities for the first time. Among them, compound 4o displayed the most potent biological activity against lymph node cells (IC₅₀ = 1.02 μM for lymph node cells and IC₅₀ = 2.17 μM for PI3Kγ). The results of apoptosis and western-blot assays demonstrated that the immunosuppressive activity of compound 4o might be mediated by the inhibition of PI3K/AKT signaling pathway. Docking simulation was performed to position compound 4o into the PI3Kγ structure active site to determine the probable binding model.     

Synthesis and biological activity of novel Schiff bases derived from metronidazole

A number of novel Schiff bases (5a–i) and (7a–d) derived from metronidazole were synthesized. Reaction of 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester toluene-4-sulfonate with 4-hydroxybenzaldehyde and with 3-hydroxybenzaldehyde in the presence of a base afforded 4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)benzaldehyde (5) and 3-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)benzaldehyde (7), respectively. The reaction of aldehydes 5 and 7 with a number of primary aromatic amines produced Schiff bases 5a–i and 7a–d, respectively. Structures of these compounds were confirmed through different spectroscopic methods such as ¹H-NMR, ¹³C-NMR, mass spectrometry, and also by elemental analyses. The prepared compounds were evaluated in vitro for their antigiardial, anti-trichomonal, antibacterial, and antifungal activities. Compounds 5e, 5g, 5i, 7a, 7b, 7c, and 7d exhibited remarkable antigiardial activity and were found to be more active than metronidazole with IC₅₀ of 7.2, 3.3, 1.5, 5.8, 4.5, 2.9, and 3.8 µg/mL, respectively. Compounds 5a and 5c also exhibited antigiradial activity with similar IC₅₀ values compared to the reference drug metronidazole with IC₅₀ of 7.2 µg/mL. The other compounds 5b, 5d, 5f, and 5 h also showed antigiardial activity but with higher IC₅₀ compared to the reference drug. Compounds were also tested for their anti-trichomonal activity, they, however, exhibited higher IC₅₀ compared to the reference drug metronidazole (7.4 µg/mL), except for compound 5a which exhibited anti-trichomonal activity with an IC₅₀ of 6.3 µg/mL. On the bases of preliminary screening, the newly synthesized compounds exhibited moderate to potent antimicrobial activities. Compound 5e inhibited the growth of Methicillin resistant Staphylococcus aureus (MRSA) and Bacillus cereus and compound 5c inhibited Candida Pathogenic fungus at 50 μg/mL compared with the positive control (Nystatin) which inhibits Candida at 25 μg/mL.     

Dimeric pyrrolidinoindoline-type alkaloids with melanogenesis inhibitory activity in flower buds of Chimonanthus praecox

A methanol extract of the flower buds of Chimonanthus praecox (L.) Link (Calycanthaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. From the extract, five dimeric pyrrolidinoindoline alkaloids and four sesquiterpenes were isolated, together with 16 known compounds. Among them, (?)-chimonanthine (1, IC₅₀ = 0.93 μM), (?)-folicanthine (2, 1.4 μM), and (?)-calycanthidine (3, 1.8 μM) showed potent inhibitory effects without notable cytotoxicity at the effective concentrations. The most potent alkaloid (1) inhibited both tyrosinase and tyrosine-related protein-1 mRNA expressions, to which the melanogenesis inhibitory activity would be ascribable.     

New diterpenoids with estrogen sulfotransferase inhibitory activity from Leonurus sibiricus L.

Four new diterpenoids (1–4), along with eight known diterpenoids (5–12) were isolated from the acetone extract of Leonurus herb (aerial parts of Leonurus sibiricus L.). The structures of the compounds were determined by spectroscopic methods. Among the isolated compounds, compounds 2, 3, 8, 9 and 10 showed inhibitory activity against human liver cytosol estrogen sulfotransferase (E-ST), which plays a key role in the maintenance of cellular estrogen levels. Compound 2 showed the strongest activity with an IC₅₀ value of 7.9 μM, which is comparable to the activity of the positive control, meclofenamic acid (IC₅₀ 5.4 μM).     

Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones

A series of N ⁴-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones 3a–3l was synthesized and evaluated for selected biological activities. The brine shrimp lethality bioassay was carried out to study their in vitro cytotoxicity potential and besides, their antifungal, phytotoxic and urease inhibitory effects were also investigated. Seven compounds i.e. 3a, 3d, 3f, 3g, 3h, 3j and 3k proved to be active in the brine shrimp assay, displaying promising cytotoxicity (LD₅₀ = 6.89 × 10^?5–2.79 × 10^?4 M). Amongst these, 3a and 3h were found to be the most active ones (LD₅₀ = 6.89 × 10^?5 and 9.79 × 10^?5 M, respectively). Compounds 3i, 3j and 3 k displayed moderate (40 %) antifungal activity against one or two fungal strains i.e. A. flavus and/or M. canis. In phytotoxicity assay, all the synthesized compounds, including the reference point 2m showed weak-to-moderate (15–70 %) activity at the highest tested concentration (500 μg/mL). In urease inhibition assay, compounds 3f, 3g and 3j proved to be the most potent inhibitors, demonstrating relatively a higher degree of enzymatic inhibition with IC₅₀ values ranging from 37.7 to 47.3 μM.     

Synthesis and cytotoxic evaluation of novel 2,3-di-O-alkyl derivatives of l-ascorbic acid

A new series of 2,3-di-O-alkyl derivatives of 5,6-O-isopropylidene-l-ascorbic acid were synthesized using phase transfer catalysis in aqueous media. These derivatives were screened for their superoxide radical scavenging activity and anticancer activity against human breast cancer cell line (MCF-7), leukemic cell line (HL-60), and cervical cell line (HeLa). All these derivatives exhibited enhanced scavenging effect than l-ascorbic acid except for the 4-fluorobenzyl or 2/4-chlorobenzyl alkyl group either at 3-O and/or 2-O position displayed pro-oxidant activity. These pro-oxidant derivatives (2c–e, m) exhibited potent anticancer activities against all the cell lines (IC₅₀ = 25.79–57.21 μM). However, these compounds were also cytotoxic to human normal leukemic macrophages THP-1. On the other hand, antioxidant derivatives displayed albeit slight (2k, IC₅₀ = 57.96–63.45 μM), but selective inhibitory effect toward all tumor cell lines. Thus, pro-oxidant and antioxidant properties can be used to predict the cytotoxic selectivity of drug against normal and cancer cells.     

Cytotoxic and anti-inflammatory constituents from the seeds of Descurainia sophia

A new sinapoyl glycoside, 1,3-di-O-sinapoyl-β-d-glucopyranose (1) along with 13 known compounds, including, sinapoyl glycosides (2 and 3), cardenolide glycoside (4), flavonoids (5–10), lignan (11), phenolic acids (12 and 13), and phytosterol (14), were isolated from the seeds of Descurainia sophia by chromatographic separation methods. The structures of 1–14 were determined by the interpretation of spectroscopic data as well as by comparison of that data with previously reported values. Compounds 2, 3, 5, 6, and 11 were identified in and isolated from this plant for the first time in this study. All isolates were evaluated for in vitro cytotoxic activities against seven human cancer cell lines and for in vitro anti-inflammatory potential using LPS-stimulated RAW264.7 murine macrophages. Compound 4 showed potent cytotoxicity (IC₅₀ values ranging from 0.034 to 0.596 μM) against all human cancer cell lines tested and was identified as the main active cytotoxic constituent of this plant. Compound 8 (ED₅₀ = 5.45 μM) and 11 (ED₅₀ = 10.02 μM) exerted dose-dependent inhibitory effects on NO production in LPS-stimulated RAW264.7 cells.     

Synthesis and in vitro antitumor activities of lupeol dicarboxylic acid monoester derivatives

Ten lupeol dicarboxylic acid monoester derivatives as new potent antitumor agents were synthesized and evaluated for in vitro antitumor activities against A549, LAC, HepG2 and HeLa cell lines. Among them, compounds 1–5 showed excellent antitumor activities against all tested tumor cell lines and compounds 6–10 exhibited high activities against A549, HepG2 and HeLa cells, exceeded lupeol, lupanol and doxorubicin. Compound 2 displayed the highest potent antitumor activities with IC₅₀ values of 5.78 μM against A549 cell, 2.38 μM against LAC cell, 6.14 μM against HepG2 cell and 0.00842 μM against HeLa cell.