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1.
Bioorg Chem ; 92: 103189, 2019 11.
Article in English | MEDLINE | ID: mdl-31473473

ABSTRACT

Angiogenesis is a hallmark in cancer. Most antiangiogenic agents block the action of vascular endothelial growth factor (VEGF). In clinic, patients develop hypoxia-mediated resistance consistent with vascular responses to these agents. Recent studies underlying such resistance revealed hypoxia-inducible PIM-1 kinase upregulation which promotes cancer progression. PIM-1 kinase expression is thus viewed as a new resistance mechanism to antiangiogenic agents. Hence, combining PIM kinase inhibitors with anti-VEGF therapies provides synergistic antitumor response. Inspired by these facts, the current study aims at designing novel dual VEGFR-2/PIM-1 kinase inhibitors via molecular hybridization and repositioning of their pharmacophoric features. Moreover, enhancing the cytotoxic potential of the designed compounds was considered via incorporating moieties mimicking caspase 3/7 activators. Accordingly, series of novel pyridine and thieno[2,3-b]pyridine derivatives were synthesized and screened via MTT assay for cytotoxic activities against normal fibroblasts and four cancer cell lines (HepG-2, Caco-2, MCF-7 and PC-3). Compounds 3a, 9e, 10b and 10c exhibited anticancer activities at nanomolar IC50 with promising safety, activated caspase 3/7 and induced apoptosis as well as DNA fragmentation more than doxorubicin in the four cancer cell lines. Furthermore, they exerted promising dual VEGFR-2/PIM-1 kinase inhibition and significantly exhibited higher therapeutic potential to alter the expression levels of VEGF, p53 and cyclin D than doxorubicin. Interestingly, the most active anticancer compound 10b conferred the highest dual VEGFR-2/PIM-1 kinase inhibition. Finally, their in silico ligand efficiency metrics were acceptable.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyridines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspases, Effector/metabolism , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship
2.
Bioorg Chem ; 88: 102934, 2019 07.
Article in English | MEDLINE | ID: mdl-31026720

ABSTRACT

In continuation of our research program aiming at developing new potent antimicrobial agents, new series of substituted 3,4-dihydrothieno[2,3-d]pyrimidines was synthesized. The newly synthesized compounds were preliminary tested for their in vitro activity against six bacterial and three fungal strains using the agar diffusion technique. The results revealed that compounds 7, 8a, 10b, 10d and 11b exhibited half the potency of levofloxacine against the Gram-negative bacterium, Pseudomonas aeruginosa, while compounds 5a, 8b, 10c and 12 displayed half the potency of levofloxacine against Proteus Vulgaris. Whereas, compounds 7, 10b, 10d and 11b showed half the activity of ampicillin against the Gram-positive bacterium, B. subtilis. Most of the compounds showed high antifungal potency. Compounds 3, 6, 7, 9b, 10a, 11a, 11b, 15 and 16 exhibited double the potency of clotrimazole against A. fumigatus. While compounds 3, 4, 5a, 5b, 9b, 10a, 10b, 10c, 13, 15, 16 and 18 displayed double the activity of clotrimazole against R. oryazae. Molecular docking studies of the active compounds with the active site of the B. anthracis DHPS, showed good scoring for various interactions with the active site of the enzyme compared to the co-crystallized ligand.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Molecular Docking Simulation , Pyrimidines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Aspergillus fumigatus/drug effects , Bacillus subtilis/drug effects , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Proteus vulgaris/drug effects , Pseudomonas aeruginosa/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
3.
Bioorg Chem ; 87: 821-837, 2019 06.
Article in English | MEDLINE | ID: mdl-30999135

ABSTRACT

Novel purine-pyrazole hybrids combining thiazoles, thiazolidinones and rhodanines, were designed and tested as 15-LOX inhibitors, potential anticancer and antioxidant agents. All tested compounds were found to be potent 15-LOX inhibitors with IC50 ranging from 1.76 to 6.12 µM. The prepared compounds were evaluated in vitro against five cancer cell lines: A549 (lung), Caco-2 (colon), PC3 (prostate), MCF-7 (breast) and HepG-2 (liver). Compounds 7b and 8b displayed broad spectrum anticancer activity against the five tested cell lines (IC50 = 18.5-95.39 µM). While, compound 7h demonstrated moderate anticancer activity against lung A549 and colon Caco-2 cell lines. Antioxidant screening revealed that six compounds (5a, 5b, 6b, 7b, 7h and 8b) with IC50 ranging from 0.93 to 14.43 µg/ml were found to be more potent scavengers of 2,2- diphenyl-1-picrylhydrazyl (DPPH) than the reference ascorbic acid with IC50 value of 15.34 µg/ml. Compounds 7b, 7h and 8b, when evaluated for their antioxidant activity, where found to be potent DPPH scavengers. Moreover, compound 7b displayed twice the potency of ascorbic acid as NO scavenger. Docking study was performed to elucidate the possible binding mode of the most active compounds with the active site of 15-LOX enzyme. Collectively, the purine-pyrazole hybrids having thiazoline or thizolidinone moieties (7b, 7h and 8b) constitute a promising scaffold in designing more potent 15-LOX inhibitors with anticancer and antioxidant potential.


Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Arachidonate 15-Lipoxygenase/metabolism , Lipoxygenase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Biphenyl Compounds/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Molecular Docking Simulation , Molecular Structure , Picrates/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rhodanine/chemistry , Rhodanine/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazolidines/chemistry , Thiazolidines/pharmacology
4.
Future Med Chem ; 10(18): 2155-2175, 2018 09 01.
Article in English | MEDLINE | ID: mdl-30088415

ABSTRACT

AIM: The development of a new class of antimicrobial agents is the optimal lifeline to scrap the escalating jeopardy of drug resistance. EXPERIMENTAL: This study aims to design and synthesize a series of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines, to develop agents having antimicrobial activity through potential inhibition of dihyropteroate synthase enzyme. The target compounds have been evaluated for their in-vitro antimicrobial activity. RESULTS & DISCUSSION: Compounds 5b, 5c were equipotent (minimal inhibitory concentration = 12.5 µg/ml) to ampicillin. The docking patterns of 5b and 5c demonstrated that both fit into Bacillus Anthracis dihydropteroate synthase pterin and p-amino benzoic acid-binding pockets. Moreover, their physicochemical properties and pharmacokinetic profiles recommend that they can be considered drug-like candidates. The results highlight some significant information for the future design of lead compounds as antimicrobial agents.


Subject(s)
Anti-Infective Agents/chemical synthesis , Bacillus anthracis/enzymology , Bacterial Proteins/metabolism , Dihydropteroate Synthase/metabolism , Quinazolinones/chemistry , Triazoles/chemistry , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Bacillus anthracis/drug effects , Bacterial Proteins/antagonists & inhibitors , Binding Sites , Dihydropteroate Synthase/antagonists & inhibitors , Drug Design , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolinones/metabolism , Quinazolinones/pharmacology , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacology
5.
Future Med Chem ; 10(12): 1449-1464, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29788781

ABSTRACT

AIM: Targeting apoptosis regulators such as caspases aiming at inducing apoptosis is an attractive strategy in cancer therapy. MATERIALS & METHODS: 8-substituted purine incorporating pyrazole moiety were designed, synthesized and evaluated for their anticancer and antioxidant activities. RESULTS: Compounds 7a and 8a displayed potent and selective anticancer activity against lung cancer A549 cell line with low cytotoxicity on peripheral blood mononuclear normal cells. Compounds 7a and 8a induced caspase dependent apoptotic death and DNA damage in all cancer cell lines. In addition, compounds 2, 5, 6a, 7a, 8a, 8c, 11a, 11b and 12b showed good antioxidant activity higher than that of the standard ascorbic acid. CONCLUSION: Compounds 7a and 8a can be considered promising dual anticancer and antioxidant leads inducing caspase-dependent apoptotic death and DNA damage.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Purines/chemistry , Purines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , A549 Cells , Antineoplastic Agents/chemical synthesis , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Apoptosis/drug effects , Caspases/metabolism , Cell Line, Tumor , DNA Damage/drug effects , Drug Screening Assays, Antitumor , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Purines/chemical synthesis , Structure-Activity Relationship , Triazoles/chemical synthesis
6.
Bioorg Chem ; 76: 437-448, 2018 02.
Article in English | MEDLINE | ID: mdl-29275262

ABSTRACT

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5 µg/mL vs levofloxacin 12.5 µg/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Dihydropteroate Synthase/antagonists & inhibitors , Drug Design , Quinoxalines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Catalytic Domain , Dihydropteroate Synthase/chemistry , Dihydropteroate Synthase/metabolism , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Levofloxacin/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Protein Binding , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/metabolism , Structure-Activity Relationship , Yersinia pestis/enzymology
7.
Open Med Chem J ; 11: 38-53, 2017.
Article in English | MEDLINE | ID: mdl-28553409

ABSTRACT

INTRODUCTION: Three series of pyrazole, thiazole and 1,3,4-oxadiazole, derivatives were synthesized starting from 5-amino-4-(hydrazinocarbonyl)-3-methylthiophene-2-carboxamide (2). METHODS: All compounds were investigated for their preliminary antimicrobial activity. They were proved to exhibit remarkable antimicrobial activity against Pseudomonas aeruginosa with insignificant activity towards Gram positive bacterial strains and fungi. RESULTS: In-vitro testing of the new compounds on hepatitis-C virus (HCV) replication in hepatocellular carcinoma cell line HepG2 infected with the virus utilizing the reverse transcription polymerase chain reaction technique (RT-PCR) generally showed inhibition of the replication of HCV RNA (-) strands at low concentration, while, eight compounds; 3a, 6, 7a, 7b, 9a, 9b, 10a and 11b proved to inhibit the replication of HCV RNA (+) and (-) strands at very low concentration range 0.08-0.36 µg/mL. CONCLUSION: Compounds 7b and 11b displayed the highest anti-HCV and antimicrobial activities in this study.

8.
Med Chem ; 9(8): 1099-112, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23628080

ABSTRACT

A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg).


Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Edema/drug therapy , Granuloma/drug therapy , Pain Measurement/drug effects , Pyrimidines/pharmacology , Tail/drug effects , Thiophenes/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Edema/chemically induced , Formaldehyde , Granuloma/chemically induced , Male , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Wistar , Thiophenes/chemical synthesis , Thiophenes/chemistry , Turpentine
9.
Eur J Med Chem ; 62: 341-51, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23376247

ABSTRACT

A new series of thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was synthesized. The newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activity using diclofenac Na as a reference standard. Additionally, the ulcerogenic effects and acute toxicity (ALD50) values of the active compounds were also determined. In general, the thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives exhibited better biological activities than the thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines. Collectively, the thienotriazolopyrimidine derivatives 9, 13 and 14a were proved to display distinctive anti-inflammatory activity at the acute and subacute models as well as good analgesic profile with a delayed onset of action. Moreover, they revealed good gastrointestinal safety profile and are well tolerated by experimental animals with high safety margin (ALD50 > 0.3 g/kg).


Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Edema/drug therapy , Pyrimidines/pharmacology , Thiophenes/pharmacology , Triazines/pharmacology , Triazoles/pharmacology , Analgesics/administration & dosage , Analgesics/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Dose-Response Relationship, Drug , Edema/chemically induced , Formaldehyde , Male , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Triazines/chemical synthesis , Triazines/chemistry , Triazoles/chemical synthesis , Triazoles/chemistry
10.
Open Med Chem J ; 7: 49-65, 2013.
Article in English | MEDLINE | ID: mdl-24379893

ABSTRACT

A new series 4,5-dihydrothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine-2-carboxamide was synthesized. Twenty one newly synthesized compounds were investigated for their anti-inflammatory and analgesic activity using acute and subacute formalin-induced paw edema models and diclofenac Na as a reference. The acute toxicity (ALD50) and ulcerogenic effects of the active compounds were also determined. The thienotriazolopyrimidines 10a, 10c and 11c were found to exhibit remarkable anti-inflammatory activity at both models in addition to good analgesic activity with a delayed onset of action. Moreover, the active compounds showed high GI safety level and are well tolerated by experimental animals with high safety margin (ALD50 > 0.4 g/kg). Docking study using Molecular Operating Environment (MOE) version 2008.10 into COX-2 has been made for derivatives of highest anti-inflammatory activity.

11.
Eur J Med Chem ; 55: 85-93, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22835720

ABSTRACT

Some new substituted thienopyrimidine derivatives comprising thioxo, thioalkyl and pyrazolyl derivatives as well as fused thienotriazolopyrimidine and thienopyrimidinotriazine ring systems were prepared from 3-benzyl-2-hydrazino-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide 4. The designed compounds were evaluated for their anti-inflammatory activity. Compounds 4, 9, 10 and 13 showed the highest anti-inflammatory effect compared with the reference drug diclofenac sodium.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Drug Design , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/chemistry , Chemistry Techniques, Synthetic , Edema/chemically induced , Edema/drug therapy , Formaldehyde/adverse effects , Granuloma/chemically induced , Granuloma/drug therapy , Male , Pyrimidines/adverse effects , Pyrimidines/chemistry , Rats , Triazoles/chemistry , Turpentine/adverse effects , Ulcer/chemically induced
12.
Arch Pharm Res ; 30(12): 1511-20, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18254237

ABSTRACT

In this study, we report the synthesis and antimicrobial evaluation of several new thiazolo[4,5-d]pyrimidine derivatives, namely 7-substituted amino-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 4a-e, 8, 13, 15, ethyl 2-cyano-2-(7-substituted-5-methyl-3-phenylthiazolo [4,5-d]-pyrimidin-2(3H)-ylidene)acetates 5a-b, 2-(7-substituted-5-methyl-3-phenylthiazolo[4,5-d]pyrimidin-2(3H)-ylidene)malononitriles 6a-b, 5-methyl-7-morpholino-3-phenylthiazolo[4,5-d] pyrimidine-2(3H)-one 7, and 7-[4-(1-substituted-5-phenyl-4,5-dihydro-1H-pyrazolin-3-yl)anilino]-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 10-12. Some of the tested compounds were more active against C. albicans than E. coil and P. aeruginosa, and all were inactive against S. aureus.


Subject(s)
Anti-Infective Agents/chemical synthesis , Pyrimidines/chemical synthesis , Thiazoles/chemical synthesis , Anti-Infective Agents/pharmacology , Microbial Sensitivity Tests , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology
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