Full Paper Synthesis of Some New S-Alkylated 1,2,4-Triazoles, Their Mannich Bases and Their Biological Activities Mohammad Mahboob Alam 1 , Syed Nazreen 1 , Saqlain Haider 1 , Syed Shafi 1 , Mohammad Shahar Yar 2 , Hinna Hamid 1 , and Mohammad Sarwar Alam 1 1 Department of Chemistry, Faculty of Science, Jamia Hamdard, New Delhi, India 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India A series of 1-(4-methoxyphenyl)-2-[5-{(biphenyl-4-yloxy)methyl}4-(substituted phenyl)-3-mercapto-(4H)- 1,2,4-triazol-3-ylthio)] ethanones (6a–6s) and 4-(substituted phenyl)-3-(morpholin/pyrrolidin-4- ylmethylthio)-5-(4-phenylphenoxymethyl)-4H-1,2,4-triazoles (7a–7e) were synthesized in order to obtain new compounds with potent anti-inflammatory and analgesic activity with insignificant ulceration. Among the synthesized compounds, (6c), (6e), (6g) and (6l) from triazole series and (7b) and (7e) from Mannich base series were found to exhibit significant anti-inflammatory activity with 59.69, 59.69, 64.69, 79.84, 54.54, 79.69% and 52.55, 57.50, 72.52, 83.03, 60.06, 84.08% inhibition of paw edema at 3 h and 5 h respectively, in comparison to the standard drug ibuprofen (78.93 and 82.58% at 3 h and 5 h). The active compounds were further tested for their analgesic activity and gastric ulceration study. Compounds 6g, 7b and 7e exhibited significant analgesic activity with reaction time (3.60, 3.22, 3.88 s) respectively at 60 min. without causing any gastric irritation. These compounds were also screened for their in vitro antimicrobial activity, Compounds 6f, 6g, 6h, 6l, 6o, 6p, 7a, 7b and 7c showed significant zone of inhibition against various antimicrobial stains. It is concluded that the compounds 6g, 7b and 7e possess a good spectrum of activities. Compound 7e may be considered potent for development of better anti-inflammatory agent. The antimicrobial activity revealed that most of the compounds showed moderate to significant activity. Compounds containing nitro, chloro, bromo and fluoro group showing better activity. All the compounds from 7a, 7b and 7e were active against gram positive bacteria (S. aureus). Keywords: Analgesic / Antimicrobial activity / Anti-inflammatory / Mannich base / Triazole / Ulcerogenic Received: April 6, 2011; Revised: June 7, 2011; Accepted: June 20, 2011 DOI 10.1002/ardp.201100128 Introduction Heterocycles play an important role in all spheres of life including pharmaceuticals, natural resources, veterinary, analytical reagents, agriculture products, and dyes [1]. The development of new approaches for the synthesis of novel heterocycles substituted with unique functional groups forms the basis of an extensive research activity in synthetic organic chemistry. The 1,2,4-triazole derivatives and their Mannich bases represent an important class of heterocyclic compounds which are known for their broad spectrum of biological activities including antimicrobial, anti-inflamma- tory, analgesic and many other uses [2–8]. As resistance to anti-inflammatory and antimicrobial drugs is widespread, there is an increasing demand for the identification of novel structure leads that may be of use in designing new, potent and less toxic anti-inflammatory and antimicrobial agents. Several 1,2,4-triazole and oxadiazole based antimicrobial agents have been synthesized to develop new molecular Correspondence: Prof. Mohammad Sarwar Alam, Department of Chemistry, Faculty of Science, Jamia Hamdard, New Delhi, India 110 062. E-mail: msalam@jamiahamdard.ac.in Fax: þ91-11- 26059663 Abbreviations: NSAIDs: non-steroidal anti-inflammatory drugs; HP- PLA2: human platelet phospholipase A2; CDCl 3 : deuterated chloroform; DMSO-d 6 : deuterated dimethylsulfoxide; ATCC: American Type Culture Collection; MTCC: Microbial Type Culture Collection; AIIMS: All India Institute of Medical Science; CDRI: Central Drug Research Institute; SDA: Sabouraud dextrose agar; MH: Muller Hinton; CMC: carboxymethyl cellulose. Arch. Pharm. Chem. Life Sci. 2012, 345, 203–214 203 ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim