Design, Synthesis, and Antiviral Evaluations of 1-(Substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as Nonnucleoside Analogues of 2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole

Abstract

We have recently reported that certain ribosylated polyhalogenated benzimidazoles are potent and selective inhibitors of HCMV replication at noncytotoxic concentrations. To extend the structure-activity relationship beyond these first-generation compounds, we alkylated 5,6-dichloro-2-substituted-benzimidazoles with either a series of substituted benzyl halides or (2-bromoethyl)benzene to obtain five series of nonnucleoside analogues. Evaluation of these compounds for activity against herpes viruses revealed that the new compounds were less active than the benzimidazole ribonucleosides against human cytomegalovirus (HCMV) and inactive against herpes simplex virus type 1 (HSV-1). However, as part of our broader antiviral testing, we found that some of these compounds were active against HIV. Comparisons of the biological data revealed that a chloro or bromo group was required at the 2-position for the best separation of activity against HIV and cytotoxicity. Evaluation of the most active compounds against drug-resistant HIV suggested that they act by a mechanism other than inhibition of reverse transcriptase.

Green and High Efficient Synthesis of 2-Aryl Benzimidazoles: Reaction of Arylidene Malononitrile and 1,2-Phenylenediamine Derivatives in Water or Solvent-Free Conditions

“…Ben-zimidazole derivatives are important scaffolds in medicinal chemistry due to their biological and pharmacological activities. These compounds exhibit activity against several viruses include HIV [7] [8], influenza [9], herpes (HSV-1) [10], RNA [11] and human cytomegalovirus (HCMV) [12]. They have also been employed as antihypertensive, antiviral, anticancer, antiulcer, antifungal and untihistamine [13]- [18].…”

NMR and NBO calculation of benzimidazoles and pyrimidines: Nano physical parameters investigation

“…E-mail: m_monajjemi@yahoo.com antiulcerative, anti-hypertensive, antiviral, antifungal, antitumor and antihistaminic agents, and antihelminthic agents in veterinary medicine (Spasov et al, 1999). Benzimidazole derivatives have found the appreciation in diverse therapeutic areas including antimicrobial activity Wu et al, 2003;Mollaamin et al, 2008;Ozden et al, 2005;Sztanke et al, 2006), the activity against several viruses such as HIV (Porcari et al ., 1998;Samia et al, 2006), antiallergic (Kilcig and Altanlar, 2006;Nakano et al, 1999), antioxidant, antihistaminic (Vijayakumar and Jafar Ahamed, 2010), antitubercular (Yadav and Srivastava, 2011;Kuchkguzel et al, 2001), antiasthmatic (Souness et al, 2000), antidiabetic (Senten et al, 2003;Black et al, 2005), anticancer (Pal et al, 2011;Sun et al, 2011;Kruse et al,1989;Islam et al,1991;Ramla et al,2007), antitumor (Denny et al, 1990 ;Tatsuta et al, 2005), antiulcer (Jung et al, 1993;Hazelton et al, 1995), antihelmentic (Karen, 2006), HIV-1 reverse transcriptase inhibitors (Gardiner et al, 2003), anticoagulant (Young et al, 2006), anti inflammatory (Fox et al, 2009), antibacterial (Rosowsky et al, 1997;Andrzejewska et al, 2004) , the series of biologically active benzimidazoles (AJafar et al,2009). Furthermore, these heterocycles are considered to be privileged structures by medicinal chemists.…”

Chemoselective Synthesis of 2-Aryl-1-arylmethyl-1H-benzo[d]imidazoles Using Indion 190 Resin as a Heterogeneous Recyclable Catalyst

“…In conclusion, we have developed a novel and highly efficient method for the synthesis of 2-aryl-1-arylmethyl-1H-benzo[d]imidazoles (3) in high yields from an o-phenylenediamine (1) and a wide variety of aromatic aldehydes (2) in the presence of Indion 190 resin as a heterogeneous catalyst. The mildness of the conversion, simple experimental procedure, clear reaction profiles, high yields and chemoselectivity, short reaction times and reusability of the catalyst are the noteworthy advantages of the protocol.…”

“…34 But one of the major margins of these methodologies is that they show poor selectivity in terms of Nsubstitution, which results in the formation of two compounds i.e, the formation of a 2-substituted benzimidazole along with 1,2-disubstituted benzimidazole as a mixture. [24][25][26]28,[33][34][35][36][37][38][39][40] Herein, we report the synthesis of 1,2-disubtituted benzimidazoles (3) by the reaction of an o-phenylenediamine (1) and various aromatic aldehydes (2) in the presence of Indion 190 resin (Scheme 1).…”