ORIGINAL RESEARCH Tautomerism and multiple modelling enhance the efficacy of QSAR: antimalarial activity of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl Vijay H. Masand • Devidas T. Mahajan • Paola Gramatica • James Barlow Received: 26 February 2014 / Accepted: 19 May 2014 Ó Springer Science+Business Media New York 2014 Abstract In the present study, sixty phosphoramidate and phosphorothioamidate analogues of amiprophos methyl (APM) previously reported as potential antimalarial agents were selected to build GA-MLR QSAR models to deter- mine the features that govern the antimalarial activity. In addition, field similarity analysis was performed to deter- mine the molecular fields that are responsible for the dif- ference in the activity. The two tautomeric forms, possible for the molecules in the present study, were considered to determine the effect of tautomerism on QSAR modelling. In the present analysis, a simplistic approach was employed with the assumption that all the molecules either exist in keto-type tautomeric form or in enol-type form. To get more results from QSAR analysis, multiple models were developed. All the models have been thoroughly validated according to the OECD principles. The best four- parametric GA-MLR QSAR model is with R 2 = 0.787 and R 2 ex = 0.806 for the keto form, and R 2 = 0.785 and R 2 ex = 0.770 for the enol form. In addition, optimum values for more easily interpretable descriptors like molecular weight (MW), lipophilicity (ALogP), etc., have been determined. The analysis reveals that consideration of tautomerism and multiple models development enhance the efficiency of QSAR analysis for lead optimization and for prediction of the activities of as-yet untested molecules. Keywords Antimalarial activity Á Amiprophos methyl analogues Á QSAR Á Field similarity Á Tautomerism Abbreviations GA Genetic algorithm MLR Multiple linear regression QSAR Quantitative structure–activity analysis WHO World Health Organization ADMET Absorption, distribution, metabolism, excretion and toxicity OLS Ordinary least square QSARINS QSAR Insubria Introduction The recent WHO report on malaria (http://www.who.int/ malaria/en/2013) clearly indicates that though malaria has its major presence in undeveloped and developing coun- tries from Africa, Asia and South America, yet, its ill- effects are global. This vector-borne disease is responsible for more than 2 million cases every year (http://www.who. Electronic supplementary material The online version of this article (doi:10.1007/s00044-014-1043-8) contains supplementary material, which is available to authorized users. V. H. Masand (&) Á D. T. Mahajan Department of Chemistry, Vidya Bharati College, Camp, Amravati 444 602, Maharashtra, India e-mail: vijaymasand@gmail.com; vijaymasand@rediffmail.com P. Gramatica QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Theoretical and Applied Sciences, University of Insubria, Via Dunant 3, 21100 Varese, Italy J. Barlow Department of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, Stephens Green, Dublin 2, Ireland 123 Med Chem Res DOI 10.1007/s00044-014-1043-8 MEDICINAL CHEMISTR Y RESEARCH