CP-MLR/PLS Directed Structure-Activity Modeling of the HIV-1 RT Inhibitory Activity of 2,3-Diaryl-1,3-thiazolidin-4-ones

A detailed structure‐activity relationship study of the HIV‐1 Reverse Transcriptase (RT) inhibitory activity of two series of compounds, 2‐(2,6‐dihalo phenyl)‐3‐(substituted pyridin‐2‐yl)‐thiazolidin‐4‐ones and 2‐(2,6‐Dihalophenyl)‐3‐(substituted phenyl)‐thiazolidin‐4‐ones, belonging to 2,3‐diaryl‐thiazolidin‐4‐ones in terms of physicochemical and structural descriptors have been carried out using combinatorial protocol interfaced multiple linear regression (CP‐MLR) and partial least squares (PLS) analysis. The models developed in the study indicate a preference for hydrophobic compounds for better inhibitory activity. Also, a positive regression coefficient of I2,3, an indicator descriptor meant for the joint disposition of substituents of 2,3‐diaryl moieties of thiazolidinones to address their ability in taking a butterfly like conformation, is in agreement with all earlier observations that compounds having the ability to take butterfly like conformation will be showing better inhibitory activity. The identified models suggest that the meta‐positions of 3‐aryl moiety has the ability to accommodate hydrophobic/ steric groups. The replacement of C2″ of 3‐phenyl by nitrogen resulted in 3‐pyridyl variants of these analogues. Even though from geometry point of view, the phenyls and pyridyls span almost the same structural space and steric features, presence of nitrogen in pyridyls gave them a blend of polarity, electronic features and a different hydrophobicity profile when compared to corresponding phenyl analogue. Furthermore the PLS models, developed from those descriptors took part in CP‐MLR models, indicate that most of the descriptors have almost equal influence in accounting for the variation in the activity of these compounds. This suggests that the factors responsible for the variation in the activity have been uniformly distributed across the varying centers of the molecule. The study suggests that thiazolidinones with 3‐(pyridin‐2‐yl) moiety provide scope for further substituent variation to modulate the HIV‐1 RT inhibitory activity.