ABSTRACT
PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , Phosphoinositide-3 Kinase Inhibitors , Pyrimidines/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , Class I Phosphatidylinositol 3-Kinases , Humans , Inhibitory Concentration 50 , MCF-7 Cells , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolismABSTRACT
A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a-g and 11a-g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofurans (1b) and their α,ß-unsaturated keto derivatives 6a-g and 7a-g with chlorosulfonyl isocyanate (CSI). On the other hand, N-chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a-g, and 11a-g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical-scavenging activity compared to ascorbic acid at 100 µg/mL. 4,9-Dimethoxy-5-substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 µmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 µmol/mL, respectively.
ABSTRACT
Novel series of spiro[(2H,3H)-quinazoline-2,1'-cyclohexane] derivatives (I-XVI) were synthesized and biologically evaluated as cytotoxic agents against human breast carcinoma cell lines (MCF-7) using doxorubicin as a reference drug. Most of the tested compounds displayed promising cytotoxic activity, especially derivatives V, VIb and XIb. The most active compounds were docked into the PARP-1 enzyme binding site to predict the ligand-protein binding modes. Lipinski rule of five and ADME profile suggested strongly that compounds V and VIb are promising agents as breast cancer inhibitors with drug likeness approach that have PARP-1 inhibitory activity. The structures of all newly synthesized compounds were confirmed by microanalysis and IR, 1H-NMR and mass spectral data.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Antibiotics, Antineoplastic , Binding Sites/drug effects , Breast Neoplasms/drug therapy , Cell Line, Tumor/drug effects , Doxorubicin/pharmacology , Female , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Spectrophotometry, InfraredABSTRACT
Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Cyclohexanes/pharmacology , Enzyme Inhibitors/pharmacology , Molecular Docking Simulation , Poly(ADP-ribose) Polymerase Inhibitors , Quinazolines/pharmacology , Antineoplastic Agents/chemical synthesis , Benzamides/pharmacology , Binding Sites , Breast Neoplasms/pathology , Cell Proliferation , Computer-Aided Design , Cyclohexanes/chemical synthesis , Doxorubicin/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Female , Humans , MCF-7 Cells , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/chemistry , Poly(ADP-ribose) Polymerases/metabolism , Protein Conformation , Quinazolines/chemical synthesisABSTRACT
A series of fused pyranopyrazole and pyranoimidazole, namely 5-(3,6-diamino-4-aryl-5-carbonitrile-pyrano(2,3-c)pyrazol-2-yl)sulphonyl-8-hydroxyquinolines (5a-e), 5-(6-amino-4-aryl-5-carbonitrile-pyrano(2,3-c)pyrazol-3-yl)sulphonamido-8-hydroxyquinolines (6a-e), 5-(2-thioxo-4-aryl-5-carbonitrile-6-amino-pyrano(2,3-d)imidazol-2-yl)sulphonyl-8-hydroxyquinolines (10a-e), and 5-(2-oxo-4-aryl-5-carbonitrile-6-amino-pyrano(2,3-d)imidazol-2-yl) sulphonyl-8-hydroxyquinolines (11a-e), have been prepared via condensation of some arylidine malononitriles with 5-sulphonamido-8-hydroxyquinoline derivatives 3, 4, 8 and 9. All the synthesized compounds were screened for their antimicrobial activities, and most of the tested compounds showed potent inhibition growth activity towards Escherichia coli, Pseudomonas aeruginosa (Gramnegative bacteria). Furthermore, six selected compounds were tested for their antiviral activity against avian paramyxovirus type1 (APMV-1) and laryngotracheitis virus (LTV), and the results showed that a concentration range of 3-4 µg per mL of compounds 2, 3, and 4 showed marked viral inhibitory activity for APMV-1 of 5000 tissue culture infected dose fifty (TCID(50)) and LTV of 500 TCID(50) in Vero cell cultures based on their cytopathic effect. Chicken embryo experiments show that compounds 2, 3, and 4 possess high antiviral activity in vitro with an inhibitory concentration fifty (IC(50)) range of 3-4 µg per egg against avian APMV-1 and LTV and their toxic concentration fifty (CC(50)) of 200-300 µg per egg.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Oxyquinoline/chemical synthesis , Oxyquinoline/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Chick Embryo , Chlorocebus aethiops , Cytopathogenic Effect, Viral , Escherichia coli/drug effects , Escherichia coli/growth & development , Herpesvirus 1, Gallid/drug effects , Herpesvirus 1, Gallid/growth & development , Microbial Sensitivity Tests , Molecular Structure , Newcastle disease virus/drug effects , Newcastle disease virus/growth & development , Oxyquinoline/analogs & derivatives , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Vero CellsABSTRACT
Two series of 2-phenyl-4(3H) quinazolinone derivatives have been synthesized. Most of the tested quinazolinone derivatives showed considerable potent anti-inflammatory and analgesic activity of superior GIT safety profile in experimental rats in comparing to indomethacin as reference drug. Compounds VIa, VIb were the most potent anti-inflammatory in experimental rats in comparing to indomethacin as reference drug. Docking study into COX-2 has been made for derivatives of anti-inflammatory activity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Carrageenan , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Drug Design , Edema/chemically induced , Edema/prevention & control , Female , Hot Temperature , Indomethacin/chemistry , Male , Mice , Models, Molecular , Pain Measurement/drug effects , Quinazolines/chemistry , Rats , Reaction Time/drug effects , Stomach Ulcer/chemically induced , Structure-Activity RelationshipABSTRACT
Starting from 4-(6,8-dibromo-2-phenyl-4-oxo-(4H)-quinazolin-3-yl)-benzoic acid ethyl ester (II) and its acid hydrazide III, a new series of Schiff bases IV and their cyclized products, thiazolidinones V, oxadiazole VIII, pyrazoles X-XII, pyrroles XIII-XV and other related products were synthesized. These compounds were screened for their anti-bacterial activity against Gram-positive bacteria (Staphylococcus aureus, Legionella monocytogenes and Bacillus cereus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium) and anti-fungal activity (Candida albicans and Aspergillus flavus) using paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Among the synthesized compounds 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-ethylamido benzoic acid hydrazide VIIa was found to exhibits the most potent in vitro anti-microbial activity with the MICs of 1.56, 3.125, 1.56, 25, 25 and 25 microg/ml against E. coli, S. typhimurium, L. monocytogenes, S. aureus, P. aeruginosa, and B. cereus respectively. Compound 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-methyl thioamido benzoic acid hydrazide VIIc was found to exhibit the most potent in vitro anti-fungal activity with MICs 0.78 and 0.097 microg/ml against C. albicans and A. flavus.
Subject(s)
Bacteria/drug effects , Drug Design , Fungi/drug effects , Quinazolinones/chemistry , Quinazolinones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/toxicity , Drug-Related Side Effects and Adverse Reactions , Microbial Sensitivity Tests , Quinazolinones/chemical synthesis , Quinazolinones/toxicityABSTRACT
A new series of the title compounds incorporated into diverse N and O heterocyclic moieties of pharmacoavailability as anti-inflammatory or analgesic agents, were synthesized starting with 6-bromo-2-phenyl-4H-3,1-benzoxazin-4-one (I) by its fusion with p-aminoacetophenone to give the intermediate compound, 6-bromo-2-phenyl-3-(4-acetylphenyl)-4(3H)quinazolinone (II). The one pot reaction of II with the appropriate aromatic aldehydes and anhyd. ammonium acetate in the presence of either ethyl cyanoacetate or malononitrile afforded the corresponding 2(1H)-pyridone derivatives III or 2(1H)- iminopyridine derivatives IV, respectively, while its reaction with malononitrile and aromatic aldehydes in piperdine gave the 2-aminopyrans V. Also reaction of the acetyl derivative II with different aromatic aldehydes afforded the corresponding 1,3-propen-1-one derivatives VI which underwent cyclization with hydrazines to give the corresponding pyrazoline derivatives VII and with urea or thiourea to give the pyrimidones or pyrimidinethiones VIII. Some representative examples of the new compounds showed promising anti-inflammatory and analgesic activities in experimental animals.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Quinazolinones/pharmacology , Analgesics/chemical synthesis , Animals , Anti-Inflammatory Agents/chemical synthesis , Disease Models, Animal , Ethanol/toxicity , Female , Male , Mice , Quinazolinones/chemical synthesis , Rats , Rats, Sprague-Dawley , Stomach Ulcer/chemically induced , Stomach Ulcer/prevention & control , Structure-Activity RelationshipABSTRACT
In this work, it was of interest to synthesize new series of some 2-[(E)-2-furan-2-yl-vinyl]-quinazolin-4(3H)-ones incorporated into pyrazoline, isoxazoline, pyrimidine or pyrimidine-thione ring systems at position-3 of the quinazoline ring. The antimicrobial activity and antiinflammatory effect of some of these compounds were studied.