A green expedient synthesis of pyridopyrimidine-2-thiones and their antitubercular activity Stephen Michael Rajesh a , Raju Suresh Kumar a , Lawzer Arun Libertsen a , Subbu Perumal a,⇑ , Perumal Yogeeswari b , Dharmarajan Sriram b a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science—Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Andhra Pradesh, India article info Article history: Received 12 January 2011 Revised 10 March 2011 Accepted 11 March 2011 Available online 17 March 2011 Keywords: Pyridopyrimidinethiones Pseudo four-component reactions Green synthesis Antitubercular activity abstract The pseudo four-component domino reactions of N-substituted-4-piperidones, substituted aromatic aldehydes and thiourea in the presence of solid sodium ethoxide under solvent-free conditions afforded pyridopyrimidine-2-thiones in almost quantitative yields by simply grinding for 1–2 min. at ambient temperature. The synthesized compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv. Among them, (E)-6-benzyl-8-(2,4-dichlorobenzylidene)-4-(2,4-dichlorophenyl)- 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine-2(1H)-thione (MIC 2.8 lM) displays the maximum activity, being 2.7 and 1.7 times more active than the first line antitubercular drugs ethambutol and ciprofloxacin, respectively, and less active than rifampicin and isoniazid, by 28 and 7 times, respectively. Ó 2011 Elsevier Ltd. All rights reserved. Pyrimidinone sub-structure is prevalent in many natural/syn- thetic biologically active compounds, which find applications in pharmaceutical and biochemical arena. 1 Dihydropyrimidinethi- ones (DHPMs) or 2-thiopyrimidines (2-TP) 2 find applications as antihypertensive (SQ 32926) (I), 3 a 1a -adrenergic receptor antago- nists, 4 antibacterial, antiinflammatory and antitumour agents. 5 In 2-TP, the sulfur atom serves as an interesting replacement for the oxygen atom bonded to C-2 in uridine base. 6 DHPMs can be con- verted into either 1,3-diamines or guanidines, which constitute the core structural elements commonly present in natural products (Fig. 1), exemplified by the polycyclic marine alkaloids such as crambines (II), ptilomycalin (III) and batzelladine. 7 Ptilomycalin (III) displays significant activity against a series of cancer cell lines and DNA polymerase activity of the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1 RT). 8 Batzelladines A and B (IV and V) are the first low molecular weight natural products re- ported in the literature to inhibit the binding of HIV-gp120 to the CD4 cell surface receptor protein on T-cells. 9 Monastrol (VI), with the pyrimidine-2-thione motif, specifically inhibits the motility of the mitotic kinesin Eg5. 10 Pyridopyrimidine analogues constitute a novel class of adeno- sine kinase inhibitors, 11 besides being the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R), 12 tyrosine kinase inhibitors, 13 diuretics, 14 antiviral 15a and antitumour agents. 15b,c Structure–activity studies disclose that anticancer activity of pyrimidinones and pyrimidinethiones is ascribable to the presence of (i) nitrogen heterocyclic ring and (ii) thione functionality, which generally enhance the activity. This has kindled substantial interest of researches in synthesis of new pyrimidinones and pyrimidinethiones. Tuberculosis (TB) is the leading cause of infectious disease mor- tality in the world. According to World Health Organization report (WHO), 16 in 2008, there were an estimated 8.9–9.9 million inci- dent cases of TB, 9.6–13.3 million prevalent cases of TB, 1.1–1.7 million deaths from TB among HIV-negative people and an addi- tional 0.45–0.62 million TB deaths among HIV-positive people. Further, HIV-infected patients have an elevated risk of primary or reactivated tuberculosis which may enhance HIV replication and the risk of death. The WHO has estimated that, if the present trend continues, TB could claim more than 30 million lives between 2000 and 2020. 17 In the last 50 years, only a few drugs have been approved by the Food and Drug Administration to treat TB. This discloses the difficulties associated with the discovery and clinical testing of new candidates and the absence of pharmaceutical industry research in this area. Hence, the discovery of fast-acting new drugs to effectively cure TB is imperative. As continuation of our research programme embarked on to discover potent antitubercular candidates by 1,3-dipolar cycloaddition 18 and multi-component or domino reactions, 19 we now report an atom economic, four-component, green synthesis of pyrido[4,3-d]pyrim- idine-2-thiones and their antimycobacterial activities. 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.03.045 ⇑ Corresponding author. Tel./fax: +91 452 2459845. E-mail address: subbu.perum@gmail.com (S. Perumal). Bioorganic & Medicinal Chemistry Letters 21 (2011) 3012–3016 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl