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Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents.

ABSTRACT: A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these hybrids experimentally, followed by evaluation of their ability to cause thermal denaturation of DNA and cytotoxic properties along with ADME predictions. The obtained results provided useful insights and two potential molecules were identified for further development.

SUBMITTER: Malik MS

PROVIDER: S-EPMC7988716 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents.

Malik M Shaheer MS Farooq Adil Syed S Moussa Ziad Z Altass Hatem M HM Althagafi Ismail I II Morad Moataz M Ansari Mohammad Azam MA Sajid Jamal Qazi Mohammad QM Obaid Rami J RJ Al-Warthan Abdulrahman A AA Shaik Thokhir B TB Ahmed Saleh A SA

Frontiers in chemistry 20210310

A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these h ...[more]

PMID: 33777897

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Project description:UnlabelledBackgroundBenzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116).ResultsA number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr). The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylene)benzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR) and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM).ConclusionsAll the synthesized bis-benzimidazolium salts showed potential anticancer activity. Out of them, some of these salts showed IC50 value as low as 0.1-0.2 μM. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs.

Dataset Information

Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents.

Publications

Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents.

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