ABSTRACT
Dasatinib is an important drug against chronic myeloid leukemia (CML). In this paper, we describe the preparation and anti-CML activity of 2-aminoxazole and 2-aminothiazole dasatinib derivatives. Biological activity was measured by the inhibition of proliferation of human CML K562 cells. The 2-aminoxazole derivatives had similar activities as the 2-aminothiazole derivatives. All newly synthesized compounds demonstrated more potent antiproliferative activity than imatinib. A few compounds (8b, 8c, 9b) showed nanomolar inhibitory activity, similar to that of dasatinib.
Subject(s)
Dasatinib/analogs & derivatives , Dasatinib/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dasatinib/chemical synthesis , Humans , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Eight new diaryltriazine derivatives containing 4-allylamino and 4-azido substitutes guided by molecular docking have been designed and synthesized based on our previous work. The evaluation of HIV inhibitory activity demonstrated that all compounds were potent against HIV-1 replication. The most active compound 7c exhibited activity against HIV-1 (IC50 = 0.034 micromol x L(-1), SI = 6,475) and the double mutant strain (IC50 = 9.39 micromol x L(-1)) in the micromolar range, which was more potent than nevirapine.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemical synthesis , Triazines/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Catalytic Domain , Inhibitory Concentration 50 , Molecular Structure , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Triazines/chemistry , Triazines/pharmacologyABSTRACT
A series of diaryltriazine derivatives modified at C(2) of the triazine ring with a fluorinated phenyl group has been synthesized and tested for the ability to inhibit HIV-1 replication. Most of these F-containing compounds showed low-to-moderate anti-HIV activity in MT-4 cells.
Subject(s)
Anti-HIV Agents/chemical synthesis , Fluorine/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemical synthesis , Triazines/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Cell Line , Fluorine/pharmacology , HIV-1/drug effects , Humans , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Triazines/chemistry , Triazines/pharmacologyABSTRACT
The ONIOM2 (B3LYP/6-31G (d, p): PM3) and B3LYP/6-31G (d, p) methods were applied to investigate the interaction between STI-571 and abelson tyrosine kinase binding site. The complex of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- phenyl]-benzamide (part of STI-571) and related 16 amino acid residues were found at B3LYP/6-31G (d, p) level to have hydrogen bonds and pi....pi stacking interaction, their binding energy via HAF optimization was -20.4 kcal mol(-1). The results derived from this study agreed well with the reported observation.
Subject(s)
Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-abl/chemistry , Pyrimidines/chemistry , Benzamides , Binding Sites , Hydrogen Bonding , Imatinib Mesylate , Models, Molecular , Piperazines/metabolism , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Proto-Oncogene Proteins c-abl/metabolism , Pyrimidines/metabolism , Quantum Theory , ThermodynamicsABSTRACT
A series of novel 6-naphthyloxy substituted DATA analogues bearing different substituents on the C-6 position of triazine ring were synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cells. The results demonstrated that most of the compounds in this series are potent activity against HIV-1 with moderate to high selectivity. Among these analogues, two compounds exhibited excellent effect in inhibiting HIV-1 replication at nanomolar concentration (for compound 9h: IC(50)=9.3 nM, SI=15,385; for compound 9i: IC(50)=9.4 nM, SI=14,094), which are about 15-fold more active than nevirapine. In addition, several compounds are active against both HIV-1 and HIV-2, whose mechanism may be different from typical NNRTIs.
