Contents lists available at ScienceDirect Environmental Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/etap Synthesis, in vitro and structural aspects of benzothiazole analogs as anti-oxidants and potential neuroprotective agents M. Janaki Ramaiah a, * ,1 , Divyapriya Karthikeyan a,1 , Sivagami Mathavan b , Rajesh B.R.D. Yamajala b, *, Srimathy Ramachandran a , P.Jaya Vasavi a , Nuthakki Venkata Chandana a a Functional Genomics and Disease Biology Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, 613401, Tamil Nadu, India b Organic Synthesis and Catalysis Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, 613401, Tamil Nadu, India ARTICLE INFO Keywords: Alzheimer’s disease Neuroprotection Catalase Benzothiazole Hydrogen peroxide ABSTRACT Catalase, an important antioxidant enzyme, is known to have a neuroprotective role against neurodegenerative disorder. Earlier study has focussed on benzothiazole-triazole hybrid molecules that are larger in size and mo- lecular weight and inhibit the amyloid β (Aβ)-catalase interaction thus aid in neuroprotection. Here we have synthesized the novel benzothiazole molecules with low molecular weight using One-pot methodology and assayed the neuroprotective efects of the synthesized compounds in the U87 MG cell line under H 2 O 2 induced stressed condition and compared with other cell lines such as breast cancer (MCF-7) and macrophage (RAW- 264.7) using cell viability assay. These analogs were found to enhance the neuronal cell viability and protect neuronal cells from the ROS mediated neuronal damage induced by H 2 O 2 . Furthermore, compounds 6a,6b,6c, 6d, and 7a modulate catalase and enhanced the catalase activity up to 90 % during the H 2 O 2 exposure in the U87MG cell line. These analogs (6a,6b,6cand6d) have exhibited strong binding energies of -7.39, -7.52, -6.5 and -7.1 as observed by molecular modeling studies using AutoDockTool-1.5.6. Lig Plot + program using potent analogs 6b and 6c and catalase enzyme indicated the presence of hydrophobic interactions in the catalytic site of catalase enzyme. Furthermore, a simulation study was conducted between ligand and catalase protein by DESMOND software that further strengthens these ligand and enzyme interactions. In silico ADMET study was conducted by the Swiss ADME program revealed the drug-likeliness of these analogs. The present study has identifed benzothiazole analogs such as 6b, 6c and 6d have potential catalase modulating activity and is comparable with that of known drug Valproic acid, thus help in neuroprotection. This study can be further taken up for the in vivo animal model study for the possible therapy. 1. Introduction Alzheimer’s disease (AD) as well as other neuronal disorders such as Parkinson’s, needs urgent medical attention. The treatment options in AD include small molecules that can block amyloid-beta (Aβ) interac- tions, reduction of the caspase protein expression, inhibition of the reactive oxygen species (ROS) dependent enzyme activity (Longo and Massa, 2004). ROS enhances the β-Amyloid protein level which in turn causes direct injury to the central nervous system (CNS) and induce neuronal cell death (Guo et al., 2013). In order to protect from the ill efects of ROS, cells can employ various antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and non-enzymatic anti- oxidant factors such as All-trans retinol 2, ascorbic acid, α-tocopherol, α-carotene, and glutathione, etc. (Birben et al., 2012). Antioxidants are compounds inhibit the formation of peroxides or quench the peroxide or scavenge the species that can generate per- oxides. The production of antioxidant enzymes takes place in glial cells and helps in the protection of the neuronal cells from oxidative stress (Wilson, 1997; Peuchen et al., 1997). The high amount of ROS was generated when neuronal cells were exposed to radiation or oxidative stress in SH-SY5Y neuronal cells. But the amount of ROS was drastically reduced when SH-SY5Y cells co-cultured with U-87 MG glial cells. This indicates that co-culturing of SH-SY5Y with U-87 MG glial cells can enhance the mitochondrial membrane potential by upregulating the production of antioxidant enzymes superoxide dismutase and anti- oxidant glutathione in SH-SY5Y cells (Saeed et al., 2015). https://doi.org/10.1016/j.etap.2020.103415 Received 6 February 2020; Received in revised form 5 May 2020; Accepted 19 May 2020 ⁎ Corresponding authors. E-mail address: janakiramaiah@scbt.sastra.edu (M.J. Ramaiah). 1 Equal frst authorship. Environmental Toxicology and Pharmacology 79 (2020) 103415 Available online 26 May 2020 1382-6689/ © 2020 Elsevier B.V. All rights reserved. T