Future Medicinal Chemistry Research Article 1193 Future Med. Chem. (2017) 9(11), 1193–1211 ISSN 1756-8919 part of 10.4155/fmc-2017-0037 © 2017 Future Science Ltd Aim: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Methodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in- house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation. Results: Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity. Conclusion: Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis. First draft submitted: 15 February 2017; Accepted for publication: 21 April 2017; Published online: 19 July 2017 Keywords:฀ autoimmune฀disorders฀•฀B-cell฀signaling฀•฀JAK3฀•฀molecular฀dynamics฀•฀oxindole฀ •฀SYK The autoimmune disorders have been char- acterized as complex disorders with many signaling pathways involving numerous sig- naling cytokines. These cytokines play a piv- otal role in the pathogenesis of autoimmune and inflammatory disorders [1] . The key step in immune signaling pathways is phosphory- lation of receptor subunits via activation of kinases presenting their vital role in immune cell signaling. The appropriate intracellular signaling pathways must be activated via cytokine receptors on cell surface and tyro- sine kinase transduces the first ‘outside to in’ signals to be phosphorylated following receptor binding to its ligand [2–5] . Among various kinases, members of JAK family and SYK family are essential for signaling path- ways of various cytokines and are implicated in autoimmune and inflammatory diseases like rheumatoid arthritis, psoriasis, etc. Thus, kinases of these families are potential therapeutic targets for the treatment of these disorders. Due to complexity of autoimmune disor- ders and involvement at different signaling pathways in its progression the modulation of single pathway might not be sufficient to produce desired efficacy. The multifacto- rial nature of this complex pathophysiology demands the designing of multitargeted agents acting on more than one signaling pathways simultaneously rather than only one pathway. Several kinase inhibitors have been approved by the US FDA as multitar- get agents for the treatment of cancer [6–8] . The use of multikinase inhibitors has now expanded beyond malignancies to autoim- mune disorders. In recent years, several Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation Maninder Kaur 1 , Manjinder Singh 1 & Om Silakari* ,1 1 Molecular฀Modeling฀Lab฀(MML),฀ Department฀of฀Pharmaceutical฀Sciences฀ &฀Drug฀Research,฀Punjabi฀University,฀ Patiala,฀Punjab฀147002,฀India *Author฀for฀correspondence:฀ Tel.:฀+919501542696฀ omsilakari@gmail.com For reprint orders, please contact reprints@future-science.com