Synthesis, antimicrobial activity and QSAR studies of new 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazoles Maninder Minu a, * , Ananda Thangadurai a , Sharad Ramesh Wakode a , Shyam Sundar Agrawal a , Balasubramanian Narasimhan b a Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar-3, M.B. Road, New Delhi 110 017, India b Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India article info Article history: Received 25 May 2008 Revised 28 March 2009 Accepted 15 April 2009 Available online 18 April 2009 Keywords: Hexahydroindazoles Antibacterial Antifungal QSAR abstract Antimicrobial activity of synthesized 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazole derivatives indicated that 3-(4-chlorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (6) and 3-(4-fluorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (20) were the most active compounds. Further, the results of QSAR studies indicated the importance of topological parameters 2 v and 2 v v in defining the antimicrobial activity of hexahydroindazoles. Ó 2009 Elsevier Ltd. All rights reserved. The usage of most antimicrobial agents is limited, not only by the rapidly developing drug resistance, but also by the unsatisfac- tory status of present treatments of bacterial and fungal infections and drug side effects. 1–5 Therefore, the development of new and different antimicrobial drugs is a very important objective and much of the research program efforts are directed towards the design of new agents. Hexahydroindazole, a novel heterocyclic compound has been reported to have antimicrobial 6,7 and anti-inflammatory activities. 8,9 QSAR models are mathematical equations relating chemical structure to a wide variety of physical, chemical and biological properties. In view of above, and as a part our composite programme of ra- tional drug design 10–23 in the present study, we report the synthe- sis, antimicrobial and QSAR studies of hexahydroindazole derivatives. The synthetic approach to obtain 3-substituted-3,3a,4,5,6,7- hexahydro-2H-indazoles (1–3) and 2,3-disubstituted-3,3a,4,5,6,7- hexahydro-2H-indazoles (4–21) followed the reaction shown in Scheme 1. We accomplished the synthesis of substituted benzylidene cyclohexanones by the reaction of cyclohexanone with p-substi- tuted benzaldehydes in the presence of ethanolic sodium hydrox- 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.04.052 * Corresponding author. Tel.: +91 11 29551321; fax: +91 11 29554503. E-mail address: maninderminu@rediffmail.com (M. Minu). O CHO O NaOH/EtOH MeOH NH 2 NH 2 N N H N N SO 2 SO 2 Cl + R 2 R 2 R 2 Pyridine R 2 4-21 1-3 R 1 R 1 1) R 1 = H, R 2 = Cl 2) R 1 = H, R 2 = F 3 ) R 1 = H, R 2 = OCH 3 4) R 1 = C 6 H 5 , R 2 = Cl 5) R 1 = CH 3 , R 2 = Cl 6) R 1 = 4-NO 2 C 6 H 4 , R 2 = Cl 7) R 1 = C 10 H 7 , R 2 = Cl 8) R 1 = 4-ClC 6 H 4 , R 2 = Cl 9) R 1 = 4-CH 3 C 6 H 4 , R 2 = Cl 10) R 1 = C 6 H 5 , R 2 = F 11) R 1 = CH 3 , R 2 = F 12) R 1 = C 10 H 7 , R 2 = F 13) R 1 = 4-CH 3 C 6 H 4 , R 2 = F 14) R 1 = C 6 H 5 , R 2 = OCH 3 15) R 1 = CH 3 , R 2 = OCH 3 16) R 1 = 4-NO 2 C 6 H 4 , R 2 = OCH 3 17) R 1 = C 10 H 7 , R 2 = OCH 3 18) R 1 = 4-ClC 6 H 4 , R 2 = OCH 3 19 ) R 1 = 4-CH 3 C 6 H 4 , R 2 = OCH 3 20) R 1 = 4-NO 2 C 6 H 4 , R 2 = F 21) R 1 = 4-ClC 6 H 4 , R 2 = F Scheme 1. Scheme for syntheses of hexahydroindazole derivatives. Bioorganic & Medicinal Chemistry Letters 19 (2009) 2960–2964 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl