A set of 15 indolylpyrimidine derivatives with their antibacterial activities in terms of minimum inhibitory concentration against the gram-negative bacteria Pseudomonas aeruginosa and gram-positive Staphylococcus aureus were selected for 2D quantitative structure activity relationship (QSAR) analysis. QSAR was performed using a combination of various descriptors such as steric, electronic and topological. Stepwise regression method was used to derive the most significant QSAR equation for predicting the inhibitory activity of this class of molecules. The best QSAR model was further validated by a leave one out technique as well as by the random trials. A high correlation between experimental and predicted inhibitory values was observed. A comparative picture of behavior of indolylpyrimidines against both of the microorganisms is discussed. 1. Introduction Pseudomonas aeruginosa (PA), a gram-negative pathogen, has been known as a major cause of hospital acquired infection and antimicrobial resistance [1, 2]. Pseudomonas aeruginosa is responsible for various infectious cases such as nosocomial pneumonia urinary tract infections, surgical wound infections, and bloodstream infections [3]. Structural differences exist between cell walls of gram-positive and gram-negative bacteria. Gram-positive bacteria have more peptidoglycan layers as compared to gram-negative bacteria. Therefore the cell wall of gram-positive bacteria is thicker than the cell wall of gram-negative bacteria. Gram-negative bacterial cell wall is different from gram-positive bacterial cell wall by having an outer membrane of lipoproteins that covers the peptidoglycan layer. The outer membrane of gram-negative bacteria is made up of phospholipids, lipoproteins, and lipopolysaccharides. The outer membrane is negatively charged and helps prevent the bacteria from being phagocytosed by macrophages. The outer membrane provides protection from effects of antibiotics, digestive enzymes, and heavy metals. Many chemical entities work as antibacterial agents by inhibiting the DNA synthesis of cell wall by blocking the enzymes such as DNA gyrase and dihydrofolate reductase and even inhibiting enzymes processing the development of peptidoglycan layer [4, 5]. Approach of antibacterial drug is initially a surface phenomenon. The wall of gram-positive and gram-negative bacteria will resist the surface interaction. Therefore there is a difference in antibacterial activity of chemical entity towards gram-positive and gram-negative bacteria. In the present work, we have made an attempt to differentiate the
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