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Synthesis, Cytotoxicity and Molecular Docking Studies of the 9-Substituted 5-Styryltetrazolo[1,5-c]quinazoline Derivatives.

ABSTRACT: In this paper, we describe the synthesis of the 5-styryltetrazolo[1,5-c]quinazolines substituted at the 9-position with a 4-fluorophenyl ring directly or via a conjugated ?-spacer (C=C or C?C bond) based on the 6-bromo-4-chloro-2-styrylquinazoline scaffold. The structures of the synthesized compounds were characterized based on a combination of ¹H-NMR, 13C-NMR, IR and high resolution mass spectral data as well as microanalyses. The tetrazoloquinazolines were evaluated for potential in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) and cervical cancer (HeLa) cells. The anti-proliferative assays demonstrated that the 9-bromo-5-styryltetrazolo[1,5-c]quinazoline 3a and 9-bromo-5-(4-fluorostyryl)tetrazolo[1,5-c]quinazoline 3b exhibit significant cytotoxicity against both cell lines. A carbon-based substituent at the 9-position resulted in complete loss of cytotoxicity against both cell lines except for the 5,9-bis((E)-4-fluorostyryl)tetrazolo[1,5-c]quinazoline 4e, which was found to exhibit comparable cytotoxicity to that of Melphalan (IC50 = 61 ?M) against the MCF-7 cell line with IC50 value of 62 ?M. Molecular docking against tubulin (PDB:1TUB) showed that compounds 3a, 3b and 4e bind to the tubulin heterodimer. Binding involves hydrogen bonding for 3a and 3b and halogen interactions for 4e.

SUBMITTER: Mphahlele MJ

PROVIDER: S-EPMC6150304 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Synthesis, Cytotoxicity and Molecular Docking Studies of the 9-Substituted 5-Styryltetrazolo[1,5-c]quinazoline Derivatives.

Mphahlele Malose J MJ Gildenhuys Samantha S Parbhoo Nishal N

Molecules (Basel, Switzerland) 20171026 11

In this paper, we describe the synthesis of the 5-styryltetrazolo[1,5-<i>c</i>]quinazolines substituted at the 9-position with a 4-fluorophenyl ring directly or via a conjugated π-spacer (C=C or C≡C bond) based on the 6-bromo-4-chloro-2-styrylquinazoline scaffold. The structures of the synthesized compounds were characterized based on a combination of ¹H-NMR, <sup>13</sup>C-NMR, IR and high resolution mass spectral data as well as microanalyses. The tetrazoloquinazolines were evaluated for poten ...[more]

PMID: 29072619

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Project description:Background:In search of effective antimicrobial and cytotoxic agents, a series of indole hybridized diazenyl derivatives (DS-1 to DS-21) was efficiently prepared by condensation of diazotized p-aminoacetophenone with indole or nitroindole followed by reaction with different aromatic/heteroaromatic amines of biological significance. The synthesized derivatives were characterized by various spectroscopic techniques. Methodology:The antimicrobial evaluation of DS-1 to DS-23 was done by tube dilution method against various pathogenic bacterial and fungal strains. The active antimicrobial derivatives were further evaluated for cytotoxicity against human lung carcinoma cell line (HCT-116), breast cancer cell line (MDAMB231), leukemic cancer cell line (K562), and normal cell line (HEK293) by MTT assay using doxorubicin as the standard drug. The test derivatives were additionally docked for the B-subunit of enzyme DNA gyrase from E. coli at the ATPase binding site to study the molecular interactions using Schrodinger maestro v11.5 software. Results and discussion:Most of the synthesized derivatives have shown high activity against Gram-negative bacteria particularly E. coli and K. pneumonia with MIC ranging from 1.95 to 7.81 ?g/ml. The derivatives have demonstrated very less activity against tested Gram positive bacterial and fungal strains. The derivatives DS-14 and DS-20 have been found to active against breast cancer cell line and human colon carcinoma cell line having IC50 in the range of 19-65 µg/ml. All the derivatives were found to less potent against leukemic cancer cell line. The synthesized derivatives have revealed their safety by exhibiting very less cytotoxicity against the normal cell line (HEK-293) with IC50?>?100 µg/ml. Most of the active derivatives have shown good docking scores in comparison to the standard drugs against DNA gyrase from E. coli. Further ADME predictions by Qikprop module of the Schrodinger confirmed these molecules have drug like properties. Conclusion:The derivatives DS-14 and DS-20 have shown potential against Gram-negative bacteria and breast cancer cell line and can be used as a lead for rational drug designing of the antimicrobial and cytotoxic agents..

Dataset Information

Synthesis, Cytotoxicity and Molecular Docking Studies of the 9-Substituted 5-Styryltetrazolo[1,5-c]quinazoline Derivatives.

Publications

Synthesis, Cytotoxicity and Molecular Docking Studies of the 9-Substituted 5-Styryltetrazolo[1,5-c]quinazoline Derivatives.

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