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Background: Natural product-inspired synthesis is a key incorporation in modern diversity-oriented synthesis to yield biologically novel scaffold. Inspired by b-carboline fused system, we have designed molecules with multi ring fused scaffold by modifying the tricyclic pyrido[3,4-b]indole ring with imidazo[1,2-a]isoquinoline. Methods: A highly convergent approach with new C–N and C–C bond formation to synthesize multiring fused complex scaffold imidazo[1,2-a]isoquinolinies as fluorophores. N-nucleophile-induced ring transformation of 2H-pyran-2-one followed by in situ cis-stilbene-type oxidative photocyclization yielded new C–C bond formation without additional oxidant. The cytotoxicity, effective concentrations, and the mode of action of the synthesized analogs were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),, plaque reduction, time of addition, and reverse transcript-ase Polymerase Chain Reaction (PCR). Results: Novel imidazo[1,2-a]isoquinoline analogs were prepared, and the results revealed that trans isomer of cyclo-propyl analog (EC 50 35 and 37.5 mg/ml) and trans isomer of citric acid salt of phenyl analog (EC 50 38.2 and 39.8 mg/ml) possess significant anti-Herpes Simplex Virus (HSV) activity with selectivity index of >10. The kinetic study demonstrated that both the analogs inhibited HSV-1F and HSV-2G at 2–4 h postinfection. Finally, western blot and reverse transcriptase PCR assays revealed that both the analogs suppressed viral immediate early transcription. Conclusion: Novel imidazo[1,2-a]isoquinoline analogs were synthesized from pyranone with appropriate amines. Two compounds showed better antiviral profile on HSV-infected Vero cells, compared to the standard drug acyclovir (ACV). Overall, we discovered a promising scaffold to develop a nonnucleoside lead targeting the viral immediate early transcription for the management of HSV infections.
Medicinal Chemistry Research, 2011
Ethyl 2,4-dioxo-4-(p-chloro)phenylbutyrate 2 obtained by condensation of 4-chloroacetophenone with diethyl oxalate was converted to 5-(4-chlorophenyl)-1phenyl-1H-pyrazole-3-carbohydrazide 5 and 5-(4-chlorophenyl)isoxazole-3-carbohydrazide 6 in good yields. Treatment of 5 or 6 with phenylisothiocyanate and reaction of the resulting thiosemicarbazide 7 or 8 with chloroacetic acid and 4-fluorobenzaldehyde, phenacyl bromides gave the corresponding 4-thiazolidinone 9 or 10 or 1,3-thiazoles 11 or 12, respectively. While the intramolecular cyclization of 7 or 8 in concentrated sulfuric acid afforded 1,3,4-thiadiazoles 13 or 14. The reactivity of hydrazide 5 or 6 towards fluorinated aldehyde, hydrazonoyl chloride, and b-ketoester was studied to give fluorinated hydrazones, bishydrazones, and pyrazoles 15-23. The newly synthesized compounds were screened for their antiviral activity, and compound 19 reduced the number of viral plaques of Herpes simplex type-1 (HSV-1) by 69%. The detailed synthesis and spectroscopic and biological data are reported.
Synthesis, antiviral activity and molecular modeling of oxoquinoline derivatives
Bioorganic & Medicinal Chemistry, 2009
In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure–activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R2 and R3 for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its : (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski ‘rule of five’, (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives.
Synthesis of Imidazo[1,2-a]pyridines as Antiviral Agents
Journal of Medicinal Chemistry, 1998
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structureactivity relationship is discussed.
Archives of Pharmacal Research, 2012
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 5sulphonamido-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.
Organic and medicinal chemistry letters, 2012
ABSTRACT: BACKGROUND: Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c). RESULTS: A known synthetic approac...
Evaluation of cytotoxic potential of newly synthesized antiviral aminopyrazoloquinoline derivatives
International journal of biomedical science : IJBS, 2007
In the present study, we screened newly synthesized antiviral aminopyrazoloquinoline derivatives for cytotoxic potential in human normal and breast cancer cell lines using apoptosis as biomarker. These derivatives and the well known antiviral drug, acyclovir, were incubated with the normal (MCF-10A, MCF-12A) and cancer (MCF-7, MDA-MB-231) cell lines at 10, 50 and 100 μM for 72 h at 37°C. Both the parent compounds and their sugar derivatives were found to be differentially cytotoxic in various cell lines. MCF-7 cells were more or less completely resistant to all these compounds while MDA-MB-231 cells were significantly killed by apoptosis. The methoxy derivative of aminopyrazoloquinoline (compound 3) was found to be the most cytotoxic in the normal breast epithelial cell lines (MCF-10A and MCF-12A) and MDA-MB-231 cell lines at 100 μM killing over 90% of the cells with up to 80% apoptosis. Interestingly MCF-7 cells showed only up to 50% killing at 100 μM dose with less than 20% apopto...
Iranian Journal of Pharmaceutical Research, 2022
Background: The emergence of drug resistance to the existing antibacterial and anti-HIV-1 therapeutics has posed an urgent medical need to develop new molecules. We describe in this regard, a series of novel N'-arylidene-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide derivatives with anti-HIV-1 and antibacterial activities were designed and synthesized in this study. Methods: The synthesized compounds were evaluated for the blocking of both the IN ST process and cell-based HIV-1 replication. The synthesized compounds were also examined for in vitro antibacterial activities using the minimum inhibitory concentration (MIC) assay. Results: The results revealed the moderate antibacterial activity of the synthesized compounds. Moreover, no significant integrase inhibitory and anti-HIV-1 activities were observed for the synthesized compounds at concentrations < 100 µM. Conclusions: According to the docking analyses, the orientation of the designed scaffold in the active site of integrase is similar to the other inhibitors of the HIV integrase and can be regarded as an acceptable template for further structural modification to improve potencies.
European Journal of Medicinal Chemistry, 2011
Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4 0 ,3 0 :-1,2]pyrimido[4,5-b] quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4 0 ,3 0 :1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3 0 ,2 0 :1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD 50 values in the low micromolar to nanomolar concentration range.