In vitro anti-plasmodial activity of new synthetic derivatives of 1-(heteroaryl)-2- ((5-nitroheteroaryl)methylene) hydrazine

Objective: To evaluate new compounds synthesized by integrating quinoline, quinazoline, and acridine rings with the active moiety of (5-nitroheteroaryl) methylene hydrazine. Methods: A new series of compounds (1a, 1b, 2a, 2b, 3a, and 3b) were synthesized and evaluated for cytotoxicity against COS-7 cells using the MTT assay. In vitro anti-plasmodial activity of the compounds was measured against CQ-sensitive (3D7) and CQ-resistant (K1) Plasmodium (P.) falciparum strains. β-hematin assay was performed to assess the inhibitory effects of β-hematin formation for new compounds. Results: The synthetic compounds had anti-plasmodial activity against blood-stage of 3D7 [IC

New Derivatives of (E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styryl quinazolin-4(3H)-one: Searching for New Antifungal and Antibacterial Agents

Objective: The objective of the paper was to evaluate the antifungal and antibacterial potential of new derivatives of ((E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styryl quinazolin-4(3H)-one. Materials and Methods: Various syntheses of (E)-3-(5-(substitutedaminomethyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one derivatives have been synthesized by reacting 2-substituted benzoxazin-4-one with (E)-2-(4-Substituedstyryl)-4H-benzo[d] [1,3]oxazin-4-one. All synthesized compounds have been characterized by the infrared, 1HNMR, and mass spectral analysis. Proposed compounds have been evaluated for antifungal and antibacterial activity. The antimicrobial activity of synthesized compounds (QNM-1 to QNM-15) has been carried through the serial dilution method. For bacterial screening, bacterial species were taken includes Staphylococcus aureus (MTCC-96), Bacillus subtilis (MTCC-441), Pseudomonas aeruginosa (MTCC-424), and Escherichia coli (MTCC-40). Norfloxacin (1-Ethyl-6-fluoro-1,4,dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid) was used as the standard drug for antibacterial study. For antifungal screening, the following fungal species were used includes Aspergillus niger (MTCC-281), Candida albicans (MTCC-227), and Fusarium oxysporum (MTCC-284). Clotrimazole was selected as a standard drug for antifungal study. Results and Discussion: QNM-1, QNM-2, QNM-3, QNM-5, QNM-7, QNM-9, QNM-12, QNM-14, and QNM-15 were the most active compounds [Table 1] in the synthesized series which were active against both Gram-positive and Gram-negative organisms by the antibacterial screening. In the case of antibacterial activity, the presence of electronegative group (Cl, Br, F, and NO2) at both R may enhance the activity when they are p-substituted, but the compounds QNM-6 (R1=-C6H5Br (o); Ar=-C6H5), QNM-10 (R1 = -C6H5F (o); Ar= -C6H5F), QNM-11 (R1 =-C6H5NO2 (p); Ar=-C6H5F), and QNM-4 (R1 =-C6H5F (m); Ar=-C6H5) with given substitution may result in diminishing the activity. In case of antifungal activity, compounds QNM-1, QNM-5, QNM-7, QNM-9, QNM-11, QNM-12, QNM-14, and QNM-15 were the most active compounds in the synthesized series which were active against both Gram-positive and Gram-negative organisms. In that series, compounds QNM-14, QNM-11, QNM-5, and QNM-7 have shown the highest activity. Compounds QNM-3, QNM-6, QNM-10, and QNM-13 have the least active. This result has also concluded that o-substituted compounds, i.e., -C6H5Cl(o), -C6H5Cl (m), -C6H5Br(o), -C6H5F (o), -C6H5F (p) at R1 position my resulted in diminishing or lower the activity

2,4-Substituted Quinazoline As Jak2 Inhibitor: Docking And Molecular Dynamics Study

Objective: The involvement of Janus kinase2/signal transducer and activator of transcription (JAK2/STAT3) pathway reported in various solid tumors made authors study the conformational changes of JAK2-3e complex which was previously reported with a moderate percentage of In-vitro JAK2 inhibition. Methods: In this present study Compound 3e was reported with a moderate percentage of inhibition of JAK2 protein selected for performing molecular docking and molecular dynamics studies to elucidate the conformational changes with JAK2-3e complex. Docking studies were performed using ChemSketch to draw the structure of the compound and optimized/energy minimized using the Ligprep module of Schrodinger suite, employing optimized potentials for liquid simulations (OPLS-2005) force field. Molecular dynamics simulations were performed for 10 ns for complex using TIP4PEW water solvent model and neutralized by adding sodium ions. Results: Docking studies of Compound 3e which has been reported as one of the effective cytotoxic agents and a moderate percentage of In-vitro JAK2 inhibition among the series, showed H-bond interaction with leucine 855, serine936, aspartine994. Dock score and Ligand binding energy with protein suggested compound 3e has shown-4.049,-66.003 kcal/mol respectively. Molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition. The Root means square deviation (RMSD) pattern of both protein and ligands in the JAK2-3e complex observed to be different over 10 ns simulation. In the JAK2-3e complex, an exponential increase in RMSD of Cα and side-chain amino acids is observed during the first 1-3 ns simulation and is stabilized till 10 ns. During the 10 ns simulation, ligand 3e seems to be stable in the complex with an overall deviation<1 Å, despite a drastic increase between 1-3 ns. The ligand RMSD plot suggests that the ligand 3e remained intact within the binding site of the protein and longer time period simulation may elucidate the binding pattern and fate of ligand 3e. Conclusion: Results from molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition by 2, 4 disubstituted quinazoline compound that is N’(2-(4-nitrophenyl)quinazoline-4-yl) isonicotinohydrazide) and their binding phenomenon. Molecular docking studies further supported the elucidation of binding patterns of the molecules in the JAK-2 protein environment. Further simulations with a longer time period may provide deeper insights into ligand interactions in the protein environment. It is noteworthy to use compound 3e as a new scaffold for further development of multifunctional compounds.

3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

To develop novel and more potent quinazoline–phosphoramidate mustard conjugates as epidermal growth factorreceptor (EGFR) inhibitor, three-dimensional quantitative structure-activity relationship [comparative molecularfield analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)] combined with moleculardocking were performed. A series of 13 compounds in the training set gave q2 values of 0.577 and 0.537, as well as r2values of 0.926 and 0.921 for CoMFA and CoMSIA models, respectively. The contour maps that were produced by theCoMFA and CoMSIA models revealed that steric, electrostatic, and hydrophobic fields were crucial in the inhibitoryactivity of quinazoline–phosphoramidate derivatives. Based on the CoMFA and CoMSIA models, several novel EGFRinhibitors were designed, which established crucial interactions at the ligand binding domain of EGFR. Nearly, 100ns MD simulation indicated the stability of the designed compounds at 100 ns, while molecular mechanics-PoissonBoltzmann surface area calculation showed that the designed compound had a higher affinity than that of the parentcompound.

Synthesis and antitumor activities of 4-（N-aryl）amino-6-long chain alkoxy pteridine derivatives / 中国药科大学学报

A series of 4-(N-aryl)amino-6-alkoxyl pteridine derivatives was designed and synthesized via the bio-isostere principle using anti-cancer drugs with quinazoline cores as lead compounds.The proliferative inhibitory activities of the synthesized compounds against tumor cells A549,KG1a and HGC-27 were also performed by MTT assay.Using methyl 3-aminopyrazine-2-carboxylate as the starting material,12 target compounds(7a-7l)were synthesized through six-step reaction, and characterized by 1H NMR, 13C NMR and MS.It was showed that antitumor activity of pteridines with 2-chloro-5-nitro-anilino substituted in position 4 was more potent than that of others.The activity of compound 7b on A549 cells(IC50=11.55 μmol/L)was closely approximate to that of positive control gefitinib(IC50=5.95 μmol/L).IC50values of compound 7k on three cell lines were all close to those of gefitinib.A 2-chloro-5-nitro-anilino fragment was contained in preferred compounds which might be modified for further investigation.

Research progress in quinazoline derivatives with anticancer activity / 中国药学杂志

Quinazoline ring, as a key skeleton structure, can produce a variety of biological activities after combining with multi-kinds of biological macromolecules. Quinazoline compounds have played particularly important roles in the discovery of anticancer drugs. The progress in quinazoline derivatives with anticancer activity was reviewed in this paper. Quinazoline compounds were classified into five types according to different substituent groups. The bioactivities of substituent groups containing quinazoline ring were discussed. And the development trend as well as the prospect of quinazoline derivatives with anticancer activity is summarized.

New Production of Antibacterial Polycyclic Quinazoline Alkaloid, Thielaviazoline, from Anthranilic Acid by the Marine-Mudflat-Derived Fungus Thielavia sp

The microbial transformation of anthranilic acid (1) by the marine-mudflat-derived fungus Thielavia sp. produced an antibacterial polycyclic quinazoline alkaloid, thielaviazoline (2). The stereostructure of the metabolite was assigned based on detailed spectroscopic data analyses including comparison of the NMR (¹H and ¹³C) data with those of reported compound (2). Compound 2 displayed in vitro antimicrobial activity against methicillin-resistant and multidrug-resistant Staphylococcus aureus (MRSA and MDRSA), with minimum inhibitory concentrations (MICs) of 6.25 and 12.5 µg/mL, respectively. Compound 2 also showed potent radical-scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) with an IC₅₀ of 11 µM, which was more active than the positive control, L-ascorbic acid (IC₅₀, 20.0 µM).

Advance in research for afatinib and its analogues, the multi-target tyrosine kinase inhibitor / 中国药学杂志

OBJECTIVE: To review the lastest research progress afatinih and its analogues, which are multi-target tyrosine kinase inhibitor. METHODS: By consulting references, the synthesis afatinib, the design, synthesis and antitumor activity its analogues are summarized, the antitumor activity, structure-activity relationship, pharmacokinetic research, adverse reaction are also summarized. RESULTS: The research progress afatinib and its analogues was comprehensively summarized. CONCLUSION: Although afatinib has much adverse reaction, it still has a good prospect and its analogues may be worth further studying.

Synthesis, spectral and antimicrobial studies of some transition metal(II) complexes with schiff base 3-[(2-Hydroxy-6-Methoxyquinolin-3- Ylmethylene)-Amino]-2-Methyl-3h-Quinazoline-4-One.

The Complexes of the type ML2 and M¢L [where M= Cu(II), Co(II), Ni(II) and Mn(II); M¢= Zn(II), Cd(II) and Hg(II)] with the Schiff base ligand (HMeOQMAMQ) L=3-[(2-hydroxy-6-methoxyquinolin-3-ylmethylene)- amino]-2-methyl-3H-quinazoline-4-one, have been synthesized. Their characterizations have been done by elemental analysis, conductance data, magnetic susceptibility measurements, 1H NMR, electronic, IR, ESR and X-ray studies. Ligand field parameters of some of the complexes have also been calculated. On the basis of spectral studies, the complexes of Zn(II), Cd(II) and Hg(II) have been assigned tetrahedral geometry, where as complexes of Co(II), Ni(II) and Mn(II) have been assigned octahedral geometry, The complex of Cu(II) has been assigned distorted octahedral geometry. The Schiff base ligand and its complexes have also been screened for their antimicrobial activity against selected fungi and bacteria. The antimicrobial results indicate that the metal complexes act as better antimicrobial agents as compared to the Schiff base ligand.

Structure anti-inflammatory activity relationship and biochemical evaluation of some novel triazoloquinazoline and triazinoquinazoline derivatives containing sulfacetamide moiety.

This study was carried out to evaluate the structure activity relationship and biochemical effects of some novel of anti-inflammatory triazoloquinazolines and triazinoquinazolines containing sulfacetamide moiety. Some of the newly synthesized compounds 4-17 showed good anti-inflammatory activities. Also, the median lethal doses (LD50s) of compounds 8, 10 and 17 in mice were 370, 338 and 295 mg/100g b.w., respectively. Oral administration of compounds 8, 10 and 17 to the rats at dose of 300 mg/kg.b.w. for 10 days showed non-significant changes in liver enzymes SGOT, SGPT, ALP, LDH, γ –GT, SOD and GPx and blood GSH and serum TBARs as compared with the control group. But, administration of indomethacin orally to the rats at a concentration of 600 mg/kg b.w daily for 10 days to rats showed significant increase in serum SGOT, SGPT, ALP, LDH, γ –GT and TBARs and significant decrease in blood GSH, SOD and GPx. These findings suggest that compounds 8, 10 and 17 exhibited good anti-inflammatory activity and more safe on rat liver enzymes.