CoMFA studies and in vitro evaluation of some 3-substituted benzylthio quinolinium salts as anticryptococcal agents

Abstract

The 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) molecular modeling technique or Comparative Molecular Field Analysis (CoMFA) has been used to design analogs of the natural product cryptolepine (1). Twenty-three compounds with their in vitro biological activities (IC50 values) against C. neoformans were used to generate the training set database of compounds for the CoMFA studies. The cross-validated q2, non-cross-validated r2, and partial least squares (PLS) analysis results were used to predict the biological activity of 11 newly designed test set compounds. The best CoMFA model produced a q2 of 0.815 and an r2 of 0.976 indicating high statistical significance as a predictive model. The steric and electrostatic contributions from the contour map were interpreted from the color-coded contour plots generated from the PLS model and the active structural components for potency against C. neoformans were determined and validated in the test set compounds. The 3-substituted benzylthio quinolinium salts (4) that make up the test set were synthesized and evaluated based on the predicted activity from the CoMFA model and the results produced a good correlation between the predicted and experimental activity (R = 0.82). Thus, CoMFA has served as an effective tool to aid the design of new analogs and in this case, it has aided the identification of compounds equipotent with amphotericin B, the gold standard in antifungal drug design.

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

“…Under normal conditions, values larger F mean that fewer explanatory variables and more target properties are acquired from a model, which implies that the model is more statistically significant [ 33 ]. In general, the CoMFA and CoMSIA models with the optimal statistics are determined by the highest Q 2 , the lowest SEE and the fewest OPN, which is applied to generate the final model [ 34 ]. The statistical results derived from the ligand-based strategy are listed in Table 1 .…”

Structure–activity relationship (SAR) and preliminary mode of action studies of 3-substituted benzylthioquinolinium iodide as anti-opportunistic infection agents

“…Each of the resulting 3-(substituted benzyl)thio quinolinium target compounds was predicted using the previously developed CoMFA model. [20] The experimentally determined IC 50 , MIC and MFC values for C. neoformans, C. albicans and A. fumigatus for compounds 9a–v , are listed in Table 1. Amphotericin B, the gold standard antifungal agent, and fluconazole served as the positive controls.…”

“…[19] More recently, we reported the successful use of the 3D-QSAR molecular modeling method of CoMFA to predict the activity of a set of synthetic antifungal compounds with a high cross-validated correlation ( q 2 ) of 0.815. [20] Subsequently, the model was validated to predict the activities of designed compounds prior to their synthesis and their biological activities have been shown to correlate very well with the CoMFA predicted activities (R = 0.80). [20] This model has inspired the design and the synthesis of the compounds in this manuscript.…”

“…[20] Subsequently, the model was validated to predict the activities of designed compounds prior to their synthesis and their biological activities have been shown to correlate very well with the CoMFA predicted activities (R = 0.80). [20] This model has inspired the design and the synthesis of the compounds in this manuscript.…”

Efficient Synthesis of 7H‐Chromeno[3,2‐c]quinolin‐5‐ium Salts and Quinolin‐4‐ones through Acid‐Promoted Cascade Reaction of 3‐Formylchromones and Anilines

“…Quinoliniums are the quaternary ammonium salts of quinolines, containing a special N ‐heteroaromatic cation. This core structure is present in natural products such as alkaloid cryptolepine [1] and nitidine [2] (Figure 1). Quinolinium salts have attracted much interest as essential scaffolds found in many biologically active molecules, [3–5] pharmaceuticals, [6–7] and material applications [8–11] .…”