A facile synthesis and microtubule-destabilizing properties of 4-(1H-benzo[d]imidazol-2-yl)-furazan-3-amines

• Published in: European journal of medicinal chemistry Vol. 94; pp. 237 - 251
• Main Authors: Stepanov, Andrei I., Astrat'ev, Alexander A., Sheremetev, Aleksei B., Lagutina, Nataliya K., Palysaeva, Nadezhda V., Tyurin, Aleksei Yu, Aleksandrova, Nataliya S., Sadchikova, Nataliya P., Suponitsky, Kyrill Yu, Atamanenko, Olga P., Konyushkin, Leonid D., Semenov, Roman V., Firgang, Sergei I., Kiselyov, Alex S., Semenova, Marina N., Semenov, Victor V.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 13.04.2015; Elsevier
• Subjects: 3T3 Cells; Animals; Antimitotic Agents - chemical synthesis; Antimitotic Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzoimidazolfurazanamines; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Cytotoxicity; Dose-Response Relationship, Drug; Humans; Inhibitors of tubulin polymerization; Life Sciences & Biomedicine; Mice; Microtubules - drug effects; Microtubules - metabolism; Models, Molecular; Molecular Structure; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacology & Pharmacy; Science & Technology; Sea urchin embryo; Sea Urchins - cytology; Sea Urchins - drug effects; Structure-Activity Relationship; PERDMICHPMBHRV-UHFFFAOYSA-N; POBNLFRIWCSOHE-UHFFFAOYSA-N; YVTIHRHBOBWHMW-UHFFFAOYSA-N; Cytotoxicity; BSLHOVZJGBQZDF-UHFFFAOYSA-N; XYFRCWVUPQNXMZ-UHFFFAOYSA-N; PTBMKLKUBYBLLL-UHFFFAOYSA-N; RGRSJUDQBXOCQG-UHFFFAOYSA-N; HCRQPXYLXXLKPT-UHFFFAOYSA-N; USCMSNZSZMKFOZ-UHFFFAOYSA-N; GNLVSCJDSUIBIB-UHFFFAOYSA-N; DNIGTZAOKTVRFC-UHFFFAOYSA-N; SIIDSPAVAUAIKA-UHFFFAOYSA-N; BXEHQFPFWOTMJM-UHFFFAOYSA-N; ROJIDUVOWRJHNV-UHFFFAOYSA-N; RKDKILJBYDCMPH-UHFFFAOYSA-N; ITWVPIOKFJWICI-UHFFFAOYSA-N; CZSWDLNVZBRZKA-UHFFFAOYSA-N; VEIXGJJDBJNXAF-UHFFFAOYSA-N; SEPADQGIHYVCEY-UHFFFAOYSA-N; PFJXDDCCRPPNQO-UHFFFAOYSA-N; JEZDHFUMFRMOCT-UHFFFAOYSA-N; QKVYMKSSFTYUSX-UHFFFAOYSA-N; UYSGWDWFIIHUDV-UHFFFAOYSA-N; LUGSNZJELBRNBF-UHFFFAOYSA-N; TZLBNPUVYLIKBI-UHFFFAOYSA-N; BQWHYOZURVCWAC-UHFFFAOYSA-N; RMPHMFUQPJQPIV-UHFFFAOYSA-N; VJOOBHOMPNDIDV-UHFFFAOYSA-N; SDIZCGINDNHBLW-UHFFFAOYSA-N; OIIBRYKPFULYFU-UHFFFAOYSA-N; JNYFYRLBJURWIM-UHFFFAOYSA-N; XZUZJWQEXZVERE-UHFFFAOYSA-N; TZLIWLOOSNBFLW-UHFFFAOYSA-N; DEVGDHZTXPMYFB-UHFFFAOYSA-N; OVKMKVJRZIKUQA-UHFFFAOYSA-N; NSIJURZMDSCFBL-UHFFFAOYSA-N; WKKYLFJMGFCKCS-UHFFFAOYSA-N; KKRITRGZHRKHJY-UHFFFAOYSA-N; CPRADZBJYGDHHF-UHFFFAOYSA-N; WSBTYNZJYPKBEA-UHFFFAOYSA-N; IQRFVILUHDVBMW-UHFFFAOYSA-N; NDHUFPMRSFLODQ-UHFFFAOYSA-N; RZZZQERCJNXUSH-UHFFFAOYSA-N; METATGUBLXSXLL-UHFFFAOYSA-N; PAMMUBFLEAQXAD-UHFFFAOYSA-N; MGSAXHIPSUZVSJ-UHFFFAOYSA-N; YTDOYRCXWVUHEE-UHFFFAOYSA-N; IKAGJZAPUHQEDX-UHFFFAOYSA-N; YHMRMWKWYJSBBR-UHFFFAOYSA-N; SAR; NXJBDHFOPXHKFG-UHFFFAOYSA-N; SNAHHWCKTZHBIF-UHFFFAOYSA-N; FHVYFQDZXQLDDO-UHFFFAOYSA-N; ZIHIDNWPEZFEMR-UHFFFAOYSA-N; XXHBNBJXGFWHPY-UHFFFAOYSA-N; Benzoimidazolfurazanamines; IBHOGLKQQCTLJE-UHFFFAOYSA-N; KVBHPKVLGQRTBA-UHFFFAOYSA-N; BDDPDOGLMHMIGJ-UHFFFAOYSA-N; ZTQIQQGRCNJUPF-UHFFFAOYSA-N; NZFDJDVIQMMRQZ-UHFFFAOYSA-N; Sea urchin embryo; YITVNTKWKUCSCF-UHFFFAOYSA-N; AKLVHSDPCVIBFL-UHFFFAOYSA-N; GFFHAHNMJVVJEG-UHFFFAOYSA-N; JMSNVUTXNCLSSL-UHFFFAOYSA-N; BIFA; ZBENILHHARJIIG-UHFFFAOYSA-N; BKGOWPYQEFOGAO-UHFFFAOYSA-N; AOLLHGYQIPWYEK-UHFFFAOYSA-N; WQUAQUGDKPBPKW-UHFFFAOYSA-N; NYXWDBXITLXZCG-UHFFFAOYSA-N; RZHUNSKDGQTPNX-UHFFFAOYSA-N; Inhibitors of tubulin polymerization; XUYDLORMICPNES-UHFFFAOYSA-N; QEPDSNAEMKSMGN-UHFFFAOYSA-N; DEEHBEBRLYOUMG-UHFFFAOYSA-N; LAQLCMYZQGUKFA-UHFFFAOYSA-N; WFXICEVOMNRSBI-UHFFFAOYSA-N; ZFXIJHLHQLACMF-UHFFFAOYSA-N; NMKPJSWDTJPRCH-UHFFFAOYSA-N; JDOHQJAEXBDMOS-UHFFFAOYSA-N; KJWUNIIUHITOKP-UHFFFAOYSA-N; KNJOGMJHNSVZCC-UHFFFAOYSA-N; LXADAVBNVFYEBW-UHFFFAOYSA-N; OWOBXUZZDLQWRD-UHFFFAOYSA-N; VZSANIPPAPURMC-UHFFFAOYSA-N; LNYBIGROTZXBRU-UHFFFAOYSA-N; ILVNNMOVPPCHLU-UHFFFAOYSA-N; SEA-URCHIN EMBRYO; BAL27862; POTENT; BENZOXAZOLES; AGENTS; TUBULIN; BENZIMIDAZOLES; BENZOTHIAZOLES; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.02.051

A series of 4-(1H-benzo[d]imidazol-2-yl)-furazan-3-amines (BIFAs) were prepared in good yields (60–90% for each reaction step) via a novel procedure from aminofurazanyl hydroximoyl chlorides and o-diaminobenzenes. The synthetic sequence was run under mild reaction conditions, it was robust and did not require extensive purification of intermediates or final products. Furthermore, there was no need for protection of reactive moieties allowing for the parallel synthesis of diverse BIFA derivatives. Subsequent biological evaluation of the resulting compounds revealed their anti-proliferative effects in the sea urchin embryo model and in cultured human cancer cell lines. The most active compounds showed 0.2–2 μM activities in both assay systems. The unsubstituted benzene ring of the benzoimidazole template as well as the unsubstituted amino group in the furazan ring were essential prerequisites for the antimitotic activity of BIFAs. Compound 57 bearing the 2-chlorophenyl acetamide substituent at the nitrogen atom of the imidazole ring was the most active molecule in the examined set. [Display omitted] •A series of benzoimidazolyl furazanamines were prepared via a novel procedure.•The synthesis was run under mild conditions.•Evaluation for antitubulin activity in the sea urchin embryo model.•Unsubstituted benzene ring and furazan amino group were essential for activity.•The compounds showed cytotoxicity in NCI60 anticancer drug screen.