Synthesis and bioactivity of novel triazole incorporated benzothiazinone derivatives as antitubercular and antioxidant agent Mubarak H. Shaikh a , Dnyaneshwar D. Subhedar a , Manisha Arkile b , Vijay M. Khedkar b,c , Nandadeep Jadhav b , Dhiman Sarkar b , Bapurao B. Shingate a,⇑ a Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India b Combi Chem Bio Resource Centre, National Chemical Laboratory, Pune 411 008, India c School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa article info Article history: Received 20 August 2015 Revised 3 November 2015 Accepted 20 November 2015 Available online 28 November 2015 Keywords: 1,2,3-Triazole Antitubercular Antioxidant Docking study ADME prediction abstract In search of new active molecules against Mycobacterium tuberculosis (MTB) H37Ra and M. bovis BCG,a small focused library of benzothiazinone based 1,2,3-triazoles has been efficiently prepared via click chemistry approach. Several derivatives were found to be promising inhibitors of MTB and M. bovis BCG characterized by lower MIC values (27.34–29.37 lg/mL). Among all the synthesized compounds, 6c and 6e is the most active compound against MTB and M. bovis BCG. The compounds were further tested for anti-proliferative activity against HeLa, A549 and A431 cell lines using MTT assay and showed no sig- nificant cytotoxic activity at the maximum concentration evaluated. Further, the synthesized compounds were found to have potential antioxidant activity with IC 50 range = 14.14–47.11 lg/mL. Furthermore, to rationalize the observed biological activity data, the molecular docking study also been carried out against a potential target MTB DprE1, which revealed a significant correlation between the binding score and biological activity for these compounds. The results of the in vitro and in silico study suggest that the triazole incorporated benzothiazinone may possess the ideal structural requirements for further develop- ment of novel therapeutic agents. Ó 2015 Elsevier Ltd. All rights reserved. Tuberculosis (TB), caused by the pathogen Mycobacterium tuber- culosis (MTB) is one of the most infectious cause of mortality world- wide. The pathogenic synergy between TB and HIV is alarming. Moreover, TB is frequently occurs in human immunodeficiency virus (HIV)/AIDS patients. In 2013, according to World Health Organization (WHO), 1.5 million deaths were reported due to TB, out of which 0.36 million people were infected with both HIV and TB. Worldwide, the proportion of new cases with multidrug- resistant tuberculosis (MDR-TB) was 3.5% and has not changed compared with recent years. 1 Despite the availability of effective anti-TB drugs, such as isoniazid and rifampicin, there is serious problem emergence as MTB developed resistance not only against the first line drug but also second line drugs. 2 Recently, a more dangerous and completely incurable form of TB has also been reported in Italy, Iran and more recently in India 3 known as totally drug resistance tuberculosis (TDR). TDR-TB strain has been shown to be resistant to all the first line, second line and third line anti-TB drugs. Therefore, there is an urgent need to develop novel anti-TB agents, which are synthetically feasible, have fewer side effects and shorter duration of treatment. Although, several new compounds are currently in different stages of clinical trials, 4 only one new drug bedaquiline has been recently approved by FDA for its use in drug resistance TB. 5 The Bacillus Calmette-Guerin (BCG) is an attenuated derivative of a virulent strain of Mycobacterium bovis which has been used as a vaccine against MTB, as a recombinant vehicle for multivalent vaccines against other infectious diseases, and as cancer immunotherapy. 6 The disease caused by BCG in humans, especially those with cellular immunodeficiencies. 7 Therefore, the ability to rapidly and specifically identify BCG is clinically important. BCG is genetically and phenotypically similar to other strains of M. bovis and to other species of the M. tuberculosis complex (M. tuberculosis, M. africanum and M. microti). 8 Oxidative stress is the major cause of tissue inflammation in tuberculosis. During illness, due to the poor dietary intake of micronutrients, free radicals burst from activated macrophages and anti-tuberculosis drugs. If these free radicals were not neutralized by the antioxidants they can leads toward the pulmonary inflammation. 9 These antioxidant exerts their effects by scavenging or preventing the generation of reactive oxygen species (ROS) 10 which can protect the formation of free radicals and retard the progress of pulmonary inflammation. http://dx.doi.org/10.1016/j.bmcl.2015.11.071 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +91 240 2403312; fax: +91 240 2403113. E-mail address: bapushingate@gmail.com (B.B. Shingate). Bioorganic & Medicinal Chemistry Letters 26 (2016) 561–569 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl