Design of Novel 4-Aminobenzofuroxans and Evaluation of Their Antimicrobial and Anticancer Activity

Elena Chugunova 1,2,* , Almir Gazizov 1,2,* , Marina Sazykina 3 , Nurgali Akylbekov 4,* ,
Anastasiya Gildebrant 3 , Ivan Sazykin 3, Alexander Burilov 1,2, Nurbol Appazov 4,5 ,
Shorena Karchava 3, Maria Klimova 3, Alexandra Voloshina 1 , Anastasia Sapunova 1,
Syumbelya Gumerova 1 , Ayrat Khamatgalimov 1 , Tatiana Gerasimova 1, Alexey Dobrynin 1,
Olga Gogoleva 2 and Vladimir Gorshkov 2
1 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of
Sciences, Kazan, Tatarstan 420088, Russia; burilov@iopc.ru (A.B.); sobaka-1968@mail.ru (A.V.);
microbi@iopc.ru (A.S.); syumbelya07@mail.ru (S.G.); ayrat_kh@iopc.ru (A.K.); tatyanagr@gmail.com (T.G.);
aldo@iopc.ru (A.D.)
2 Laboratory of Plant Infectious Diseases, FRC Kazan Scientific Center of Russian Academy of Sciences, Kazan,
Tatarstan 420111, Russia; gogolewaoa@yandex.ru (O.G.); gvy84@mail.ru (V.G.)
3 Southern Federal University, Rostov-on-Don 344090, Russia; submarinas@list.ru (M.S.);
siniamida@gmail.com (A.G.); zebra-sis@yandex.ru (I.S.); skarchava@sfedu.ru (S.K.);
mzhuravleva@sfedu.ru (M.K.)
4 Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda
University, Kyzylorda 120014, Kazakhstan; nurasar.82@mail.ru
5 I. Zhakaev Kazakh Scientific Research Institute of Rice Growing, Kyzylorda 120008, Kazakhstan
* Correspondence: chugunova.e.a@gmail.com (E.C.); agazizov@iopc.ru (A.G.); nurgali_089@mail.ru (N.A.);
Tel.: +7-843-272-7324 (E.C.); +7-843-272-7324 (A.G.); +7-724-223-1041 (N.A.)
Received: 20 October 2020; Accepted: 29 October 2020; Published: 5 November 2020


Abstract: A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic
amines fragments was achieved via aromatic nucleophilic substitution reaction of
4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the
factors aecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored
both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained
compounds has been evaluated and some of them were found to suppress eectively bacterial biofilm
growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates
of M. nivale. The eect of some benzofuroxan derivatives is likely to be more universal against dierent
varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer
activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity
towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity
towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing
aromatic amines fragments in their structure are promising candidates for further development both
as anti-cancer and anti-microbial agents.
Keywords: benzofuroxan; anti-cancer activity; apoptosis; bacterial biofilm; fungistatic activity;
quantum chemical calculations