Synthesis of a novel series of 4-arylpiperazinyl derivatives linked to a 2-(pyridin-3-yl)-1H-benzimidazole as new Delavirdine analogues

A síntese de uma série de arilpiperazinas ligadas à estrutura 2-(piridina-3-il)-1H-benzo[d] imidazol, através de um linker alquílico é relatada. Os novos derivados 1-(2-(4-arilpiperazina-1il)alquil)-2-(piridina-3-il)-1H-benzimidazol são estruturalmente relacionados à droga anti-HIV-1 Delavirdina e pertencem à família bis(heteroaril)piperazinas (BHAPs), um conhecido grupo de inibidores da transcriptase reversa HIV-1.


Introduction
Non nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) such as nevirapine, have been approved for the treatment of acquired immune deficiency syndrome (AIDS). 1 A major limitation of such treatment is the emergence of resistant virus with specific mutations in the reverse transcriptase (RT) gene. Therefore, the development of new active compounds has been the focus in many laboratories. 2  The efforts along this line led to the discovery of the bis-(heteroaryl)piperazine (BHAP) class of HIV-1 reverse transcriptase inhibitors. 4,5 Delavirdine, a BHAP derivative and first-generation NNRTI is displayed in Figure 1. 6 A variety of papers reporting the synthesis of Delavirdine analogues have been published up to the date. 7,8 However, structural modifications have been mainly focused on the 4-heteroaryl piperazyne moiety, being the substitution of the indol ring by other heterocycles less explored. 9 To the best of our knowledge, there is not any report about the synthesis of BHAPs containing benzimidazole as the heterocyclic framework. The main reason we adopted to use benzimidazole framework, is the well known bioisosteric equivalence of this ring, respect to 1(H)-Indole. Besides, preliminary docking studies carried out by our research group supported this bioisosteric change.
In this paper, we describe the synthesis of a new BHAP series combining two scaffolds, the 2-(pyridin-3-yl)-1Hbenzo [d]imidazole and substituted 4-arylpiperazines linked by methilenic spacers. The structural similitude between Delavirdine and the target compounds is displayed in Figure 1.

Results and Discussion
The Delavirdine analogues 5(a-k) were prepared according to the retrosynthetic strategy displayed in scheme 1. We developed a general and useful synthesis of substituted 4-arylpiperazinyl ethyl (propyl) alcohol scaffolds 3(a-k), which were utilized for coupling reactions with 2-(pyridin-3-yl)-1H-benzo[d]imidazole 4 leading to the desires substituted target compounds.
The intermediate arylpiperazinyl building blocks 3(a-k) were synthesized as follows. Treatment of the appropriate substituted arylpiperazine 1 with 1-bromoethanol (1-bromopropanol) in acetone at room temperature, gave the corresponding alcohols 2(a-k) in 40-54% yield along with the ethers 6 and 7 as minority side products (Scheme 2). The alcohols were easily purified by column chromatography, showing the characteristics hydroxyl spectral signals (IR:3590-3644 cm -1 ; 1 H-NMR, broad singlet d OH 2.86-3.87). The 1 H-NMR spectra displayed also the piperazine and the methylene protons at high field (d CH2 1.70-3.87), supporting the presence of these functions.
Reaction of the alcohols 2a-k with mesyl chloride and triethylamine in dichlorometane at 0 °C provided the respective mesylated alcohols 3a-k in moderate to good yields (Scheme 2). The mesylation was mainly deduced by their IR spectra (absence of the hydroxyl signal and presence of the two characteristic SO 2 signals at 1348 and 1173 cm -1 ) and their 1 H-NMR spectra which displayed the singlet for the methyl group protons at d: 2.78-3.08 ppm. Interestingly, the chloroethyl arylpiperazines 3b' and 3e' were obtained instead of the expected mesylated products.  Alkylation of the obtained benzimidazole moiety was readily accomplished using NaOH as the base in acetonitrile. As is shown is scheme 4, coupling of the benzimidazole anion with substituted alkyl arylpiperazines in the presence of triethylamine in acetonitrile at room temperature for 12 h, provided target compounds 5(a-k) ( Table 1)     In summary, a convenient method for the synthesis of 1-(2-(4-Arylpiperazin-1-yl)alkyl)-2-(pyridin-3yl)-1H-benzimidazole derivatives has been provided. Further studies on the application will be reported in due course.

Experimental
All organic solvents used for the synthesis were of analytical grade. IR spectra were recorded on a Brucker Vector 22 spectrophotometer using KBr discs. 1 H and 13 C NMR spectra were obtained on Brucker APC-200 spectrometer using tetramethylsilane as internal reference. Column chromatography was performed on Merck silica gel 60 (70-230 mesh). Thin layer chromatography separations were performed on Merck Kiesselgel 60 (70-230 mesh). Elemental analyses were carried out on a FISONS EA 1108 CHNS-O analyzer.