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Synthesis and Structure Elucidation of New Benzimidazole Amidoxime Derivatives Yeni Benzimidazol Amidoksim Türevlerinin Sentezleri Ve Yapı Aydınlatmaları

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Synthesis and Structure Elucidation of New Benzimidazole Amidoxime Derivatives Yeni Benzimidazol Amidoksim Türevlerinin Sentezleri Ve Yapı Aydınlatmaları Turk J Pharm Sci 2020;17(1):108-14 DOI: 10.4274/tjps.galenos.2019.44270 ORIGINAL ARTICLE Synthesis and Structure Elucidation of New Benzimidazole Amidoxime Derivatives Yeni Benzimidazol Amidoksim Türevlerinin Sentezleri ve Yapı Aydınlatmaları Cigdem KARAASLAN* Ankara University Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey ABSTRACT Objectives: In our previous studies we synthesized some potent antiparasitic, anticancer and antimicrobial amidine derivatives. Despite all their potent activities, it is well known that due to their cationic charge, amidine derivatives pose a serious problem in terms of bioavailability. The main purpose of this study is to prepare amidoxime derivatives of previously synthesized potent amidine derivatives as prodrugs in order to increase their bioavailabilities. Materials and Methods: The targeted benzimidazole amidoximes were synthesized from their nitrile derivatives. The nitrile groups of these benzimidazole carbonitriles were converted to N-hydroxy benzamidine derivatives (amidoxime derivatives, 20-29) in the presence of NH2OH.HCI and KO-t-Bu in dimethyl sulfoxide. Structures of newly synthesized amidoxime derivatives were elucidated with 1H-NMR, 13C-NMR and some 2D NMR techniques like COSY, NOESY, HSQC and HMBC. Results: A new series of benzimidazole amidoximes were synthesized and their structural elucidations were done in this study. Conclusion: In order to solve the potential bioavailability problem of potent amidine derivatives, we prepared the prodrugs of those potent amidine derivatives as their amidoxime derivatives. In vivo studies of both previous amidine derivatives and amidoxime prodrugs of those amidines which were synthesized in this study are planned to perform in our ongoing studies. Key words: Amidoxim, amidinobenzimidazole, prodrug, 1H-NMR, 2DNMR ÖZ Amaç: Daha önce yaptığımız çalışmalarda, antiparaziter, antikanser ve antimikrobiyal etkili potent aktiviteye sahip bazı amidin türevleri sentezledik. Ancak potent aktivitelerine rağmen, amidin türevlerinin, katyonik yükleri nedeniyle biyoyararlanım açısından ciddi bir sorun oluşturduğu bilinmektedir. Bu çalışmanın temel amacı, daha önce sentezlenen etkili amidin türevlerinin biyoyararlanımlarını artırmak için, ön ilaçları olarak bilinen amidoksim türevlerini hazırlamaktır. Gereç ve Yöntemler: Hedeflenen benzimidazol amidoksimler, nitril türevlerinden hareketle sentezlenmiştir. Bu benzimidazol karbonitrillerin nitril grupları, dimetil sülfoksit içerisinde NH20H.HCl ve KO-t-Bu varlığında N-hidroksi benzamidin türevlerine (amidoksim türevleri, 20-29) dönüştürülmüştür. Yeni sentezlenmiş olan amidoksim türevlerinin yapıları ise 1H-NMR, 13C-NMR ve COSY, NOESY, HSQC ve HMBC gibi bazı 2D NMR teknikleri ile açıklanmıştır. Bulgular: Bu çalışmada yeni bir seri benzimidazol amidoxim türevi bileşik sentezlenmiş ve yapıları aydınlatılmıştır. Sonuç: Daha önceki çalışmalarımızda sentezlediğimiz amidin türevleri ile literatürlerde biyolojik açıdan etkili bulduğumuz amidin türevlerinin potansiyel biyoyararlanım problemlerini çözebilmek için, bu çalışmada söz konusu potent amidinlerin ön ilaç formları olan amidoksim türevlerini hazırladık. Etkili amidin türevleri ile bu çalışmada sentezlenen amidoksim türevlerinin in vivo çalışmalarının devam eden araştırmalarımız kapsamında yapılması planlanmaktadır. Anahtar kelimeler: Amidoksim, amidinobenzimidazol, önilaç, 1H-NMR, 2DNMR *Correspondence: E-mail: [email protected], Phone: +90 312 203 30 63 ORCID-ID: orcid.org/0000-0002-2006-5421 Received: 04.12.2019, Accepted: 16.12.2019 ©Turk J Pharm Sci, Published by Galenos Publishing House. 108 Cigdem KARAASLAN. New Amidoxime Derivatives 109 INTRODUCTION Amidoximes instead of amidines principle was first performed A biologically active compound with intended pharmacological to pentamidine and then it has been transferred to several other activity may have unwanted properties that limit its bioavailability amidine derivatives (Furamidin-Pafuramidin) (Figure 1) for or structure which negatively effect its activities in the increasing oral absorption and improving bioavailability.12-14 organism. Amidoximes are generally developed to overcome Amidoxime derivatives indicate a prodrug class used to low oral bioavailability of amidines which are pharmacologically enhance the oral bioavailability of amidine containing drugs. effective in many areas including antiparasitic,1 antimicrobial2 Because of their lower basicity and higher lipophilicity than and anticancer activities.3 amidine derivatives, they can be quickly absorbed by the Amidine derivatives which are known as DNA interactive gastrointestinal tract after oral administration.12,15 compounds, have been used in clinic for many years especially Over the past decade, we have focused our effort on the design against protozoal diseases. The most important example of of amidino benzimidazole derivatives possessing antiprotozoal this group is pentamidine (Figure 1) which has been used and anticancer activity.1,3 effectively in the treatment of several protozoal diseases Mono-di amidino 2-anilino benzimidazoles were designed, 1,4 for many years. Amidino group bearing compounds with synthesized and their antiprotozoal activities were determined similar structures such as berenil, furamidine (Figure 1) and against Trypanosoma brucei rhodesiense and Plasmodium some amidino benzimidazoles are also used as effective falciparum. In this study some of dicationic compounds (Figure antiprotozoal compounds based on their selective binding to 2a) showed almost equal activity with melarsoprol against 5 AT-rich sequences of DNA. Furthermore, it is also known that Trypanosoma brucei rhodesiense and they showed close activity these compounds have shown very good activities in anticancer with chloroquine against Plasmodium falciparum.1 therapy.6-8 Pentamidine has been emphasized as a potential Furthermore, the anticancer activities of these compounds anticancer agent also.9-11 Although amidine group is essential for with additional new analogues were studied against MCF-7 the pharmacological effect of several active compounds, their human breast adenocarcinoma cells. Some of them (Figure oral bioavailability is too low and they have several toxic effects. 2b) strongly inhibited MCF-7 cell viability compared to clinically Due to hydrophilic and very strong basic properties of amidines, used reference compounds, docetaxel and imatinib mesylate.3 after protonation they form highly mesomerically stabilized cations and so they are usually incapable of passing through Recently we reported synthesis and antimicrobial-anticancer membranes and cannot be absorbed from the gastrointestinal activities of 2-(3,4-dimethoxyphenyl) benzazoles and system after oral administration.12 In order to avoid this imidazopyridine derivatives with very important results16 some problem, several prodrug attempts have been performed on the of which bearing amidine groups (Figure 2c). amidine moiety of drugs and hydroxylation of amidine group As a part of our continuing research program, focused on to amidoxime has been found the most promising alternative. developing new antimicrobial and anticancer benzimidazole Figure 1. Chemical structures of some amidine derivatives and their amidoxime prodrugs Figure 2. Previously synthesized potent benzimidazole carboxamidines 110 Cigdem KARAASLAN. New Amidoxime Derivatives carboxamidines, we have planned to prepare prodrug structures uptake of H2 ceased. Then the Pd-C was filtered off from of some of our effective amidine derivatives which have celite and washed with ethanol several times. The filtrate was been previously reported.1,3,16 Furthermore we designed new concentrated in vacuo and the crude product was used for amidoxime derivatives according to literature including amidine further steps without crystallization. Yield, 0.67g (92%). Mp: 17,18 1 derivatives which have potent activities (Figure 2d, e). In vivo 152-154°C . H-NMR δ (DMSO-d6): 5.21 (s, 2H, -NH2), 6.86-6.90 studies of these newly synthesized benzimidazole amidoximes (m, 2H), 6.97-7.01( m, 3H), 7.06 (d, 1H, J= 8 Hz), 7.24 (t, 2H, J= 13 are planned to test efficacy in an animal model and to determine 7.6 Hz), 7.47 (s, 1H), C-NMR δ (DMSO-d6): 102.1, 116.3, 116.8, their pharmacokinetic profiles in further analysis. 118.3, 120.1, 120.8, 121.1, 129.2, 134.2, 139.3, 142.5. MS (ESI+) m/z: 209.2 (M+H, 100%). MATERIALS AND METHODS Sodium metabisulphite adduct of arylaldehyde derivatives Experimental The corresponding arylaldehydes (5 mmol) were dissolved in Uncorrected melting points were detected by a capillary melting ethanol (25 mL) and the solution of sodium metabisulfite (0.5 g) point device (Büchi B-540). The 1H, 13C, COSY (Evaluated as only in water (5 mL) was added piece by piece. Then reaction was primary neighbourhood), NOESY, HSQC and HMBC - nuclear stirred and kept in refrigerator until all precipitation finished magnetic resonance (NMR) spectra were performed by VARIAN and the resulting precipitate was filtered off and dried, and used (Agilent) MERCURY 400 MHz (Varian, Palo Alto, CA, USA) without purification for further steps. at a proton resonance frequency of 400 MHz and a carbon General synthesis of compounds 10-19 resonance frequency of 100 MHz. The optimisation of NMR spectrum was directed by Agilent Vnmr J version 3.2 revision The mixture of related 3-amino-4- (N-substituted-amino) Asoftware. The samples to be analysed (5-20 mg) were prepared benzonitriles 5-9 (1 mmol) and related sodium metabisulphite
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