Synthesis of quinoline coupled [1,2,3]-triazoles as a promising class of anti-tuberculosis agents K. Karthik Kumar a , S. Prabu Seenivasan b , Vanaja Kumar b , T. Mohan Das a,⇑ a Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India b Tuberculosis Research Centre, V.R. Ramanathan Road, Chennai 600 031, India article info Article history: Received 24 March 2011 Received in revised form 1 June 2011 Accepted 21 June 2011 Available online 28 June 2011 Keywords: Quinoline derivatives Click chemistry Cu(I) catalysed Anti-tubercular activity Saccharide triazole derivatives Mycobacterium tuberculosis H37Rv abstract A series of quinoline coupled 1,2,3-triazoles compounds have been synthesized by ‘click chemistry’ from azidomethyl quinoline with different alkynes. The efficiency and fidelity of the Cu(I)-catalyzed azide– alkyne reaction are substantiated by good yields and exclusive formation of the expected 1,4-disubsti- tuted triazole product. All the synthesized compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37Rv by luciferase reporter phage (LRP) assay. Quinoline coupled triazole sugar hybrid, 20 is the most potent compound in the series with 76.41% and 78.37% reduction calculated based on percentage reduction in Relative Light Units at 5 and 25 lg/mL, respectively. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction One of the major challenging health problems around the world is tuberculosis. Although, tuberculosis is a treatable contagious dis- ease, despite the availability of useful drugs, the disease causes about two million deaths annually due to infection by Mycobacte- rium tuberculosis. 1 Treatment of tuberculosis is a complex process due to several factors which include patients developing resistance to existing drugs, the emergence of multi drug-resistant TB (MDR- TB) and the association of human immunodeficiency virus (HIV) with TB. In particular, due to the mutation from katG and inhA, the resistance against the major anti-tuberculosis drugs such as iso- niazide has caused intractable tuberculosis. Similarly, mutation of rpoB-gene and pncA-gene has also resulted in resistance against anti-tuberculosis drugs—rifampicin and pyrizinamide, respec- tively. 2–4 Therefore, over the past few years the design of new drugs as potent anti-tuberculosis agents have been carried out. As a result, new drugs with divergent, unique structure and also with mechanism of action possibly different from that of existing drugs are urgently required. Quinolines and their analogs represent an important class of organic molecules that have attracted great deal of attention from synthetic as well as medicinal chemists due to their presence in var- ious natural products, exhibiting a wide range of physiological activities. 5–8 In particular, derivatives of 8-hydroxy-2-methylquin- oline (1) act as powerful prototypes for zinc sensors in biological systems. 9 Similarly, 4-amino-quinolines (2), with substitution at the second position qualified to be highly potent anti-HIV-1 agents. 10 In addition, imidazo[4,5-c]quinoline derivative (3), 11 and 1H-imidazo[4,5-c]quinoline-4-amine derivative (4), 12 acts as a po- tent tumor necrosis factor-a (TNF-a) suppressor and allosteric modulators of the human A 3 adenosine receptor, respectively. Fur- thermore, it is noteworthy to observe that 4-(adamant-1-yl)-2- quinolinecarbohydrazide (5) 13 (Fig. 1) displays promising activities against drug sensitive and resistant M. tuberculosis H37Rv strains. Owing to these remarkable biological activities of quinoline and its derivatives, there has been an increasing interest in the develop- ment of easy and simple methodologies for synthesizing such bio- logically active molecules. Carbohydrates are the most abundant group of natural com- pounds, and their glycoconjugates, are involved in important func- tions, such as cell–cell recognition and communication, inflam mation, immunological response, bacterial and viral infection, tumorigenesis and metastasis. 14 The saccharide portions of various classes of natural products function as key molecular recognition elements, which are important for the biological properties of the natural compounds. Moreover, carbohydrates linked to a heterocy- clic moiety are often a prerequisite for biological activity and can thus heavily influence the pharmacokinetics, drug targeting and mechanism of action. Similarly, N-heterocyclic compounds, such as [1,2,3]-triazoles are known to display wide range of biological activities. 15–17 0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.06.028 ⇑ Corresponding author. Tel.: +91 44 22202814; fax: +91 44 22352494. E-mail address: tmdas_72@yahoo.com (T.M. Das). Carbohydrate Research 346 (2011) 2084–2090 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres