benzimidazole-5-carboxylates
* The compounds referred to in the chapter are referred to elsewhere in the thesis with an C preceding the number of the compound. For example 5a-v is referred to as C5a-v elsewhere in the thesis.
Abstract
A library of 2-substituted fluorinated benzimidazoles (C5a-C5v) was synthesized by an easy, efficient, rapid and inexpensive route for the synthesis of benzimidazoles using microwave conditions. The synthesized compounds were tested for their antimicrobial and antioxidant behaviour. The benzimidazoles C5p and C5r showed strong antimicrobial (MBCs: 14-555 and 25-446 µM respectively) and antioxidant activities (IC50: 386.55 and 306.71 µM respectively) compared to the standards used for comparison. Docking studies of C5h and C5r (one inactive and one active compound) into the active site of topoisomerase II DNA-gyrase were used to explain the crucial interaction with the Mn2+ ion in the active site of the enzyme for anti-bacterial activity.
Keywords: Benzimidazole, microwave, thermal, antimicrobial, antioxidant, docking.
7.1 Introduction
The development of new, robust, efficient and environmentally friendly chemical processes for the synthesis of bis-heterocyclic compounds is needed in the pharmaceutical and chemical industries (Dua et al., 2011; Jain s et al., 2013). Greener and more sustainable chemical syntheses focus on minimal or no use of solvents or the use of water as a solvent, reduction of waste, use of ambient conditions, shortening of reaction times, and developing easy methods of product separation and purification.
Nitrogen containing compounds are important chemical compounds due to their numerous applications. The benzimidazole moiety has gained importance in recent years having anticancer, antiviral, antibacterial, antioxidant, antifungal, anthelmintic, antiparasitic, antimycobacterial, antidiabetic, antihypertensive, analgesic, antipsychotic, anticoagulant, cardiovascular, and anti- inflammatory properties (Vazquez et al., 2001; Tomic et al., 2004; Biron et al., 2006; Kuş et al., 2009; Narasimhan et al., 2010; Vyas et al., 2010; Kalyankar et al., 2012; Barot et al., 2013;
Gurvinder et al., 2013; Jain S et al., 2013; Yoon et al., 2014; Keri et al., 2015; Singla et al., 2015).
Benzimidazoles are generally synthesized by coupling reactions between o-phenylenediamines with carboxylic acids, carboxylic acid chlorides or aldehydes and in some cases esters and amides (Panda et al., 2012; Khanna et al., 2012; Prajapti et al., 2015; Saberi et al., 2015; Saleh et al., 2015;
Rithe et al., 2015; Kattimani et al., 2015; Keri et al., 2015; Carvalho et al., 2015; Azizian et al., 2016). They are also synthesized from o-phenylenediamines and reagents other than acid derivatives or aldehydes (Khanna et al., 2012). When two moles of o-phenylenediamines are reacted with dicarboxylic acid derivatives, symmetric bisbenzimidazoles are formed (Khanna et
al., 2012). These symmetric bisbenzimidazoles are also formed with o-phenylenediamines and hexachloro-2-propanone (Rezende et al., 2001) or with symmetric diacids or dialdhehydes (Khanna et al., 2012). Symmetric bisbenzimidazoles are also synthesized with [1,1'-biphenyl]- 3,3',4,4'-tetraamines and a number of different reagents (Khanna et al., 2012).
There have been numerous reports of benzimidazoles being synthesized using classical organic chemistry in the presence of Lewis acid catalysts containing Sn, Ti,Zr, Bi, In, Co, Ce, B, Zn and Hf (Zhang et al., 2007), Ir (Tateyama et al., 2016), La (Kamal et al., 2014), acetic acid (Jain et al., 2013) and p-toluenesulfonic acid (Xiangming et al., 2007; Funel et al., 2014), basic catalysts such as NaOH (Rajasekhar et al., 2010), KOH (Al-Mohammed et al., 2013), or inorganic salts for example NaHSO3 (Jain et al., 2013) and Na2S2O5 (Yoon et al., 2015). Although benzimidazoles are synthesized widely with the use of a catalyst, several of these catalysts are quite costly such as (TiCl4, Ir, HfCl4, Bi(NO3)5 and ZrCl4) (Zhang et al., 2007). Although several synthetic procedures to the benzimidazoles use non-environmentally friendly solvents such as DMF (Yoon et al., 2015), CHCl3 (Gupta Atyam et al., 2010) and toluene (Funel et al., 2014), other reported procedures have made use of greener solvents such as methanol and water (Borhade et al., 2012; Chen et al., 2012;
Rao et al., 2014).
The grinding method (Banerjee et al., 2014), ultrasound (Patil et al., 2014) and visible light promoted (Park et al., 2014) were all used to synthesize benzimidazoles without the use of a catalyst. In recent years there has been much interest in microwave syntheses (Das et al., 2012;
Gawande M et al., 2014; Jacob et al., 2012). Using microwave synthesis, benzimidazoles were synthesized without the use of catalysts and organic solvents (Abdullah et al., 2012; Eren et al.,
2014;). Its advantages are therefore that it is a green technique, cheaper, carried out in shorter times and uses less energy than conventional synthesis. Benzimidazoles were also synthesized under microwave conditions using NaHSO3 as a catalyst (López et al., 2009).
In our study, we have synthesized fluorinated benzimidazole derivatives from the o- phenylenediamine (methyl 3-amino-4-(4-fluorophenylamino)benzoate) and various substituted aldehydes using three methods, conventional organic synthesis with a sodium metabisulphite catalyst and ethanol as solvent, the grinding method with iodine as a catalyst and under microwave conditions with no catalyst or solvent, and compared the yields and reaction times of these methods. We synthesized a total of twenty-two 2-substituted fluorinated benzimidazoles (C5a- C5v) and tested them for their antimicrobial and antioxidant activity.
7.2 Experimental
7.2.1 General experimental procedures
All chemicals were supplied by Sigma-Aldrich via Capital Lab, South Africa. Organic solvents were redistilled and dried according to standard procedures. Silica gel 60 F254 plates (Merck) were used for thin layer chromatography. Crude compounds were purified by column chromatography using silica gel (60-120 mesh) and a mobile phase of varying ratios of EtOAc : Hexane. Melting points were recorded using a Stuart Scientific SMP3 apparatus. UV spectra were obtained on a Varian Cary UV-VIS spectrometer in MeOH. IR spectra were recorded on a Perkin Elmer 100 FT-IR spectrometer with universal attenuated total reflectance sampling accessory.