Showing papers in "Archiv Der Pharmazie in 2014"
TL;DR: Inhibition of human (h) carbonic anhydrase (CA) isoenzymes (hCA I, hCA II) and acetylcholine esterase (AChE) was investigated with the synthesized compounds and sulphamides 11–13 and sulphonamides 14–16 had moderate inhibition capacity toward AChE.
Abstract: Reactions of amino, aminomethyl tetralins and benzyl alcohol with chlorosulphonyl isocyanate (CSI) afforded sulphamoyl carbamates. The sulphamoyl carbamates were converted to sulphamides by palladium-catalysed hydrogenolysis. Sulphonamides were synthesized from the reactions of amines with MeSO2 Cl. Inhibition of human (h) carbonic anhydrase (CA) isoenzymes (hCA I, hCA II) and acetylcholine esterase (AChE) was investigated with the synthesized compounds. hCA I and hCA II were inhibited in the low micromolar or sub-micromolar range. The Ki values were in the range of 0.91-9.56 µM against hCA I and of 3.70-27.88 µM against hCA II. Sulphamides 11-13 and sulphonamides 14-16 had moderate inhibition capacity toward AChE. These findings suggest the novel sulphamides 11-13 and sulphonamides 14-16 as AChE and CA isoenzyme inhibitory agents.
108 citations
TL;DR: Some of the most recent findings of curcumin properties that suggest a close relationship of this antioxidant with the mitochondrial function are focused on.
Abstract: Curcumin, a phenolic compound extracted from Curcuma longa, is commonly used in Asia as a spice and pigment and has several biological functions, particularly antioxidant properties. It has been reported that curcumin exhibits bifunctional antioxidant properties related to its capability to react directly with reactive oxygen species (ROS) and also to its ability to induce the expression of cytoprotective and antioxidant proteins through the transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2). Recently, it has been postulated that the mitochondrial function and metabolism are associated with Nrf2 and that curcumin has shown activities against mitochondrial dysfunction. The damage in mitochondria has been implicated in the pathogenesis of diseases like diabetes, cancer, aging, and neurodegenerative disorders. This review focuses on some of the most recent findings of curcumin properties that suggest a close relationship of this antioxidant with the mitochondrial function.
94 citations
TL;DR: This review focuses on AMP‐activated protein kinase activation and its possible therapeutic role in the treatment of cancer.
Abstract: Recent advances in AMP-activated protein kinase (AMPK) as a target in cancer waxed and waned over the past decade of cancer research. AMPK is a cellular energy sensor, present in almost all eukaryotic cells. An elevated AMP/ATP ratio activates the AMPK, which in turn inhibits energy-consuming processes and induces catabolic events that generate ATP to restore the energy homeostasis inside the cell. Several reports have indicated that AMPK regulates several metabolic pathways and may be a potential therapeutic target for the treatment of cancer. Cancer cells have specific metabolic changes that differ from normal cells, and AMPK prevents the deregulated processes in cancer. AMPK may also act to inhibit tumor formation through modulation of cell growth, cell proliferation, autophagy, stress responses, and cell polarity. AMPK has been shown to inhibit mammalian target of rapamycin (mTOR) through tuberous sclerosis complex 2 (TSC2) phosphorylation and phosphatase and tensin homolog (PTEN), considered as central cell growth controller signals in diseases. In response to glucose deprivation, AMPK phosphorylates and activates p53, which induces cell cycle arrest in the G1/S phase of the cell cycle. AMPK has also been reported to block cyclin-dependent kinases through phosphorylation of p27(kip1) , promoting its stabilization and allowing cells to survive metabolic stress via induction of autophagy. Additionally, AMPK induces autophagy by phosphorylation and activation of eEF-2 kinase, and prevents the formation of new proteins. AMPK activators are also used for the treatment of type II diabetes and cancer. This review focuses on AMPK activation and its possible therapeutic role in the treatment of cancer.
90 citations
TL;DR: Three 1‐aminoindanes, four anilines and BnOH or t‐BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates which inhibited hCA I and II competitively in the nanomolar range.
Abstract: Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3 CO2 H afforded seven novel sulfamides. Human carbonic anhydrase (hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (Ki : 153.88 nM), while sulfamide derivative 26 showed the highest inhibitory potential against hCA II (Ki : 117.80 nM).
79 citations
TL;DR: This review shows the direction of long‐term drug/nutraceutical safety trials and provides insights for future research in this area, and covers the synthesis, usage, and biological activities of JA and its derivatives.
Abstract: In medicinal chemistry there is a growing interest in using small molecules, including plant stress hormones. Jasmonic acid (JA) and its volatile methyl ester (MJ), collectively termed jasmonates, are lipid-derived cyclopentanone compounds that occur ubiquitously and exclusively in the plant kingdom. This review covers the synthesis, usage, and biological activities of JA and its derivatives. A brief overview of the available information on JA and its features is given, followed by a detailed review of JA and its derivatives as drugs and prodrugs; the properties in plants and the synthesis in recent patents are described. This review shows the direction of long-term drug/nutraceutical safety trials and provides insights for future research in this area. Research on JA continues to be of major interest. Recent innovations offer hope for the development of new therapeutics in related fields. It is anticipated that several analogs can be advanced to preclinical and clinical studies.
75 citations
TL;DR: The inhibitory effects of diphenylmethanone derivatives 5–18 were tested on human CA and they inhibited both isoenzymes at micromolar levels, and stable conformations of 5 and 10 are more convenient for interaction with CA isoenZymes than those of the other compounds.
Abstract: Known and novel derivatives including CO, Br, and OH (benzylic and phenolic), and the corresponding benzylic alcohols of (3,4-dimethoxyphenyl)(2,3,4-dimethoxyphenyl)methanone were synthesized, and their inhibitory effects on the carbonic anhydrase (CA) isoenzymes I and II were investigated. CAs are the metalloenzymes catalyzing the reversible hydration of carbon dioxide (CO2 ) to bicarbonate (HCO3 (-) ). The inhibitory effects of diphenylmethanone derivatives 5-18 were tested on human CA (hCA, EC 4.2.1.1) isoenzymes (hCA I and hCA II) and they inhibited both isoenzymes at micromolar levels. Compounds 5 and 10 were found to be the best inhibitors against both CA isoenzymes. According to our data, compound 10 was the best inhibitor for isoenzyme hCA I (IC50 = 3.48 µM, Ki = 2.19 µM) whereas compound 5 was found to be the best inhibitor for isoenzyme hCA II (IC50 = 1.33 µM, Ki = 2.09 µM). Probably, stable conformations of 5 and 10 are more convenient for interaction with CA isoenzymes than those of the other compounds.
74 citations
TL;DR: The recent advances along with current developments as well as future outlooks for the design of novel and efficacious anticancer agents based on oxadiazole motifs are highlighted.
Abstract: Taking into account the rising trend of the incidence of cancers of various organs, effective therapies are urgently needed to control human malignancies. The rapid emergence of hundreds of new agents that modulate an ever-growing list of cancer-specific molecular targets offers tremendous hope for cancer patients. However, almost all of the chemotherapy drugs currently on the market cause serious side effects. Based on these facts, the design of new chemical entities as anticancer agents requires the simulation of a suitable bioactive pharmacophore. The pharmacophore not only should have the required potency but must also be safer on normal cell lines than on tumor cells. In this perspective, oxadiazole scaffolds with well-defined anticancer activity profile have fueled intense academic and industrial research in recent years. This paper is intended to highlight the recent advances along with current developments as well as future outlooks for the design of novel and efficacious anticancer agents based on oxadiazole motifs.
55 citations
TL;DR: The Mannich base containing compound 11 may be a source of good leads for the synthesis of lipase and urease dual inhibitors and shows moderate‐to‐good lipase inhibitory effects compared to orlistat.
Abstract: In the present study, starting compound 4 was prepared by deamination of compound 2 in the presence of hypophosphorous acid and sodium nitrite. Treatment of compound 4 with ethyl bromoacetate produced ethyl[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetate (5), which was converted to the hydrazide derivative (6) by treatment with hydrazine hydrate. The reaction of compound 6 with aromatic aldehydes resulted in the formation of arylidene hydrazides (7). Treatment of 6 with CS2 in the presence of potassium hydroxide (KOH), followed by cyclization with hydrazine hydrate, afforded 4-amino-5-{[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione (9). The condensation of 9 with appropriate aldehydes gave Schiff bases (10), which were converted into Mannich bases (11) in the presence of formaldehyde. All the synthesized compounds were screened for their anti-lipase and anti-urease activities. Compounds 7b, 7d, 11b, 11c, and 11d showed moderate-to-good lipase inhibitory effects compared to orlistat. Compounds 7b and 7d exhibited better anti-lipase activity. Furthermore, among the compounds tested, 11a and 11d were found to show high inhibitory effect against urease with IC50 values of 12.39 ± 0.35 and 16.12 ± 1.06 µg/mL, respectively. Compound 11c showed moderate inhibitory activity. The Mannich base containing compound 11 may be a source of good leads for the synthesis of lipase and urease dual inhibitors.
53 citations
TL;DR: Both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.
Abstract: Some new N-[6-indazolyl]arylsulfonamides and N-[alkoxy-6-indazolyl]arylsulfonamides were prepared by the reduction of 2-alkyl-6-nitroindazoles with SnCl2 in different alcohols, followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. The newly synthesized compounds were evaluated for their antiproliferative and apoptotic activities against two human tumor cell lines: A2780 (ovarian carcinoma) and A549 (lung adenocarcinoma). Preliminary in vitro pharmacological studies revealed that N-(2-allyl-2H-indazol-6-yl)-4-methoxybenzenesulfonamide 4 and N-[7-ethoxy-2-(4-methyl-benzyl)-2H-indazol-6-yl]-4-methyl-benzenesulfonamide 9 exhibited significant antiproliferative activity against the A2780 and A549 cell lines with IC50 values in the range from 4.21 to 18.6 µM, and also that they trigger apoptosis in a dose-dependent manner. Furthermore, both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.
35 citations
TL;DR: This study provides the development of a series of novel compounds as effective antitumor agents with apoptotic death ability with more potent antiproliferative activity than BENC‐511 against KG‐1 cells.
Abstract: 3-Nitro-2H-chromenes have recently been identified as a novel class of potent antitumor agents. In view of the favorable effects shown by sulfonylhydrazones and acylhydrazones, we designed and synthesized a series of sulfonylhydrazone- and acylhydrazone-substituted 8-ethoxy-3-nitro-2H-chromene derivatives, and evaluated their cell growth inhibition activities against A549, KG-1, A2780, and K562 cells. All the tested compounds exhibited more potent antiproliferative activity than BENC-511 against KG-1 cells. These compounds displayed IC50 values in the nanomolar range against A2780 cells. Compound 7d showed prominent cytotoxicity against K562 cells with an IC50 of 0.11 µM, which was comparable to that of BENC-511. Compound 7d arrested K562 cells at the G1 phase at high concentrations and induced apoptosis in K562 cells. Furthermore, 7d increased the levels of cleaved caspase-3, decreased the expression of bcl-2 and induced the cleavage of poly(ADP-ribose) polymerase in K562 cells. Thus, this study provides the development of a series of novel compounds as effective antitumor agents with apoptotic death ability.
34 citations
TL;DR: This work represents a critical review about relevant NDGA mechanisms, cellular effects, and signal pathways involved with possible useful effects and exerts beneficial effects in diverse diseases like cancer, renal damage, Huntington's disease, Alzheimer's disease and other neurodegenerative pathologies.
Abstract: Nordihydroguaiaretic acid (NDGA) is a phenolic compound obtained from the leaves of the evergreen desert shrub Larrea tridentata (Creosote bush), which has been used anciently in folk medicine for the treatment of multiple diseases. At the molecular level, NDGA is a potent scavenger of reactive oxygen species. Lipoxygenase inhibition by NDGA has been broadly studied over several cell models; however, NDGA exerts other antioxidant properties and cytoprotective effects in non-tumor cells, which are related with its role as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway. In contrast, in tumor cells NDGA exerts pro-apoptotic activity and anti-tumor effects. Different effects of NDGA have been observed in mitochondria, where NDGA prevents mitochondrial damage in non-tumor cells and induces loss of mitochondrial function in tumor cells. Moreover, NDGA exerts beneficial effects in diverse diseases like cancer, renal damage, Huntington's disease, Alzheimer's disease, and other neurodegenerative pathologies. This work represents a critical review about relevant NDGA mechanisms, cellular effects, and signal pathways involved with possible useful effects.
TL;DR: Two new hybrid molecules prepared by condensation of 4‐(trimethylsilylethynyl)benzaldehyde 1 with substituted o‐phenylenediamines showed a moderate inhibition of 30% in the Foa sporulation test and were examined for their in vitro antimicrobial activities against Gram‐positive and Gram‐negative bacteria and the phytopathogenic fungi.
Abstract: A novel series of hybrid molecules 4a–i and 5a–i were prepared by condensation of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne–azide cycloaddition (CuAAC) to generate the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and the phytopathogenic fungi Verticillium dahliae and Fusarium oxysporum f. sp. albedinis. 2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)methoxy)ethanol 5e showed a moderate inhibition of 30% in the Foa sporulation test.
TL;DR: 3‐halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines and fluorescence microscopy and flow cytometry analyses confirmed that the anti‐cancer effect of the most potent compounds 1c and1d occurs via apoptosis induction.
Abstract: A novel series of chalcones and flavanones discriminated by the presence of a 3,4-dimethoxyphenyl moiety in their structures were synthesized as anti-cancer agents. The cytotoxicity evaluation of the analogs against the MCF-7, MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cell lines demonstrated that the introduction of a halogen on the 3,4-dimethoxyphenyl part of both series and the attachment of a pyrrolidinylethoxy group on the C-7 position of the flavanone derivatives increased their activity. Indeed, 3-halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines. Fluorescence microscopy and flow cytometry analyses confirmed that the anti-cancer effect of the most potent compounds 1c and 1d occurs via apoptosis induction.
TL;DR: A series of 4,6‐diaryl/heteroarylpyrimidones was synthesized employing silica‐supported fluoroboric acid under solvent‐free conditions in a microwave reactor and compound VA‐25 with a pyridinyl ring as ring A and a thiophenyl ring as rings B emerged as the most potent XO inhibitor.
Abstract: Summary
A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica-supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory activity for the first time. Structure-activity relationship analyses are also presented. Among the synthesized compounds, VA-5, -9, -10, -12, -22, -23, and -25 were the active inhibitors with IC50 values ranging from 6.45 to 13.46 µM. Compound VA-25 with a pyridinyl ring as ring A and a thiophenyl ring as ring B emerged as the most potent XO inhibitor (IC50 = 6.45 µM) in comparison to allopurinol (IC50 = 12.24 µM). Some of the important interactions of VA-25 with the amino acid residues of the active site of XO were figured out by molecular modeling studies.
TL;DR: The activities suggest different modes of biological action of the compounds having nitro‐heteroaryl groups, and the 2‐hydroxyphenyl or pyridin‐2‐yl substituents, on the other hand.
Abstract: A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 μM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 μM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.
TL;DR: The new 1,2,4‐triazole‐3‐one derivatives bearing the salicyl moiety had moderate anticonvulsant activities in the maximum electroshock‐induced seizure and minimal clonic seizure models in mice, without any neurotoxic effects.
Abstract: A series of new 1,2,4-triazole-3-one derivatives bearing the salicyl moiety were synthesized by using microwave irradiation, and their chemical structures were identified by IR, (1) H NMR, (13) C NMR, elemental analysis, and LC-MS. The anticonvulsant activities of the compounds 4a-c, 4e, and 5a-e were evaluated by the Anticonvulsant Screening Program of the National Institute of Health, USA. The compounds had moderate anticonvulsant activities in the maximum electroshock-induced seizure and minimal clonic seizure models in mice, without any neurotoxic effects.
TL;DR: New hydrazone incorporated triazines were designed and synthesized using an appropriate synthetic route with regard to essential pharmacophores, and evaluated for their anticonvulsant activity through maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole‐induced seizure (scPTZ) screenings.
Abstract: New hydrazone incorporated triazines were designed and synthesized using an appropriate synthetic route with regard to essential pharmacophores, and evaluated for their anticonvulsant activity through maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole-induced seizure (scPTZ) screenings. Among the tested compounds, 4-[{2-(5-(3-chlorobenzyl)-3-phenyl-1,2,4-triazine-6-yl)hydrazono}methyl]-N,N-dimethylaniline 6k (MES ED50 54.31, scPTZ ED50 92.01) and 4-[{2-(5-(4-chlorobenzyl)-3-phenyl-1,2,4-triazine-6-yl)hydrazono}methyl]-N,N-dimethylaniline 6r (MES ED50 46.05, scPTZ ED50 83.90) emerged as the most active anticonvulsant agents having GABAergic effects. Compounds 6k and 6r also showed lesser CNS depressant effect than the standard drug carbamazepine. To obtain further insights into the binding interactions of these molecules, molecular docking studies were carried out.
TL;DR: A series of novel 1′‐[2‐(difluoromethoxy)benzyl]‐2′H,5′H‐spiro[8‐azabicyclo[3.2.1]octane‐3,4′‐imidazolidine]‐ 2′,5‐dione substituted hydantoins (5–32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data.
Abstract: A series of novel 1'-[2-(difluoromethoxy)benzyl]-2'H,5'H-spiro[8-azabicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione substituted hydantoins (5-32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data. The novel molecules were screened for anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScPTZ)-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9, 10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared to phenytoin.
TL;DR: In this article, a series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF, and the electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety led to a significantly less toxic and equally potent TNF inhibitor.
Abstract: SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.
TL;DR: In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum.
Abstract: New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.
TL;DR: A novel series of benzothiazole derivatives bearing the ortho‐hydroxy‐N‐acylhydrazone moiety showed moderate to excellent cytotoxic activity against all five tested cancer lines and indicated that the phenyl group on the 2‐hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro.
Abstract: A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50 = 0.31 µM) with IC50 values ranging from 0.24 to 0.92µM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50 = 0.41 µM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity.
TL;DR: The results indicate that compound 26 has a better EGFR tyrosine kinase inhibitory profile than compound 7, which showed relatively potent cytotoxic activity among the derivatives, against all the cell lines tested.
Abstract: In a quest for finding potent cytotoxic molecules, we have designed and synthesized a new scaffold by tagging quinazolinones with an acridone moiety. The new acridone-4-carboximide derivatives were evaluated for their cytotoxic potentials against the MCF7 breast cancer cell line and three colon cancer cell lines (LS174T, SW1398, and WiDr). Compound 26 showed relatively potent cytotoxic activity among the derivatives, against all the cell lines tested. Mechanistic studies for the selected derivatives 7, 8, 16, 17, 25, and 26 were conducted through in vitro EGFR tyrosine kinase inhibition studies. The results indicate that compound 26 has a better EGFR tyrosine kinase inhibitory profile. The in vitro EGFR inhibition data was correlated with the cytotoxic properties, and molecular docking studies were performed with regard to the receptor autophosphorylation sites of the protein kinase domain of the EGFR.
TL;DR: Among the tested compounds, 2 and 9 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin, by inhibiting the expression of uPA.
Abstract: 5-Amino-1-p-tolyl-1H-pyrazole-4-carbonitrile (1) was used for the preparation of some novel pyrazoles and pyrazolo[3,4-d]pyrimidines 2-10. Moreover, the cytotoxicity and in vitro anticancer activities of the prepared compounds were also assessed against the MCF-7 breast cancer, HepG2 liver cancer, and A549 lung carcinoma cell lines, along with investigation of the effect of the synthesized compounds on the expression of urokinase plasminogen activator (uPA). The tested compounds exhibited remarkable cytotoxic activity against MCF-7 and HepG2 cells. Among the tested compounds, 2 and 9 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin, by inhibiting the expression of uPA.
TL;DR: The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and ester as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents.
Abstract: A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents.
TL;DR: In a preliminary biological evaluation, the conjugates of lysine dendrimers and 5‐fluorouracil showed the expected advantages: stable drug release, low toxicity to normal cells, and moderate inhibition of tumor cells, implying that cell‐penetrable lysines dendrisers could be potential carriers in drug delivery of anti‐cancer medicine.
Abstract: Improving the cell penetration and enhancing the cell selectivity of drugs have been approved for overcoming the major drawbacks of chemotherapeutic agents: the toxicity to normal cells and the drug resistance in tumors. In this paper, lysine dendrimers (G1-G3) were chosen as novel cell-penetrating carriers for anti-cancer drugs based on the internalization mechanism of cell-penetrating peptides and the characteristics of dendritic peptides. After labeling with fluorescein isothiocyanate (FITC), the cell-penetrable capacity of lysine dendrimers was certified by flow cytometric analysis. In a preliminary biological evaluation, the conjugates of lysine dendrimers and 5-fluorouracil showed the expected advantages: stable drug release, low toxicity to normal cells, and moderate inhibition of tumor cells. These results imply that cell-penetrable lysine dendrimers could be potential carriers in drug delivery of anti-cancer medicine.
TL;DR: The investigated compounds were found to lower the intracellular reactive oxygen species in the H2DCFDA assay and also caused mitochondria‐dependent cell death in the MCF‐7 cell line, indicating a plausible mechanism of their anticancer effect.
Abstract: A series of 17 analogs of 1-acetyl-4,5-dihydro(1H)pyrazoles (JP-1 to JP-17) bearing two aromatic rings at positions 3 and 5, either of which ought to be heterocyclic, were synthesized and evaluated for their anti-proliferative potential against breast cancer (MCF-7 and T-47D) and lung cancer (H-460 and A-549) cell lines for the first time. JP-1-7, -10, -11, -14, and -15 were observed to exhibit significant anti-proliferative activity against MCF-7 cells. Some notions about structure-activity relationships are reported. The investigated compounds were found to lower the intracellular reactive oxygen species in the H2 DCFDA assay and also caused mitochondria-dependent cell death in the MCF-7 cell line, indicating a plausible mechanism of their anticancer effect.
TL;DR: The compounds with C11‐alkyl chains showed antifungal potency comparable to clotrimazole, and inhibit enzymes of the ergosterol biosynthesis (Δ14‐reductase and Δ8,7‐isomerase), depending on the heterocyclic scaffold and the investigated species.
Abstract: A series of N-alkyl trans-decahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized starting from the respective secondary amines by N-alkylation with alkyl bromides. The compounds with C11-alkyl chains showed antifungal potency comparable to clotrimazole, and inhibit enzymes of the ergosterol biosynthesis (Δ14-reductase and Δ8,7-isomerase), depending on the heterocyclic scaffold and the investigated species.
TL;DR: Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and antiproliferative activities against a broad variety of DNA and RNA viruses.
Abstract: Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and antiproliferative activities against a broad variety of DNA and RNA viruses. Whereas none of the compounds exhibit antiviral activity at subtoxic concentrations, antiproliferative activity was found against murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and cervix carcinoma cells (HeLa) for 4, 8, and 10.
TL;DR: A series of novel 2‐(diaryl methanone)‐N‐(4‐oxo‐2‐phenyl‐thiazolidin‐3‐yl)‐ acetamides synthesized by various Schiff bases of (4‐benzoyl‐phenoxy)‐aceto hydrazide with thioglycolic acid exhibit potent antioxidant properties, which is evident from in vitro and in silico analysis.
Abstract: A series of novel 2-(diaryl methanone)-N-(4-oxo-2-phenyl-thiazolidin-3-yl)-acetamides were synthesized by various Schiff bases of (4-benzoyl-phenoxy)-aceto hydrazide with thioglycolic acid. The structures of the newly synthesized compounds were confirmed by IR, 1H NMR, mass spectra, and C, H, N analysis. Further, all the synthesized compounds 9a–n were evaluated for xanthine oxidase (XO) inhibition and antioxidant properties. Among all the tested compounds, 9f, 9m, and 9n demonstrated potent XO inhibition of 52, 76, and 26%, respectively, compared to the standard drug allopurinol, which is evident from in vitro and in silico analysis. On the other hand, compounds 9c, 9d, and 9k exhibit potent antioxidant properties.
TL;DR: In vivo results in mice showed that seven compounds were effective in the MES or/and scPTZ seizure tests and showed higher potency and also lower neurotoxicity than the reference antiepileptic drugs such as ethosuximide and valproic acid.
Abstract: A series of 22 new N-[(4-phenylpiperazin-1-yl)-methyl]-3-methyl-pyrrolidine-2,5-dione and pyrrolidine-2,5dione derivatives were synthesized and evaluated for their anticonvulsant activities in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that seven compounds were effective in the MES or/and scPTZ seizure tests. The quantitative evaluation in both tests after i.p. administration into mice revealed that the most active compounds were N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-methyl]-3-methylpyrrolidine-2,5-dione (12) with ED50 ¼16.13mg/kg (MES), ED50 ¼133.99mg/kg (scPTZ) and N-[{4-(3,4-dichlorophenyl)-piperazin1-yl}-methyl]-pyrrolidine-2,5-dione (23 )w ith ED 50 ¼37.79mg/kg (MES), ED50 ¼128.82mg/kg (scPTZ), whereas N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-pyrrolidine-2,5-dione (24) was effective only in the MES test with ED50 ¼16.37mg/kg. These molecules showed higher potency and also lower neurotoxicity than the reference antiepileptic drugs such as ethosuximide and valproic acid.