CoMFA studies and in vitro evaluation of some 3-substituted benzylthio quinolinium salts as anticryptococcal agents.
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 Crytococcus neoformans were used to generate the training set database of compounds for the CoMFA studies. The cross-validated q(2), noncross-validated r(2), 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 q(2) of 0.815 and an r(2) 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.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Sidney
S
Bolden
Comfort A
CA
Boateng
Xue Y
XY
Zhu
Jagan R
JR
Etukala
Suresh K
SK
Eyunni
Melissa R
MR
Jacob
Shabana I
SI
Khan
Seth Y
SY
Ablordeppey
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D001487:Basidiomycota / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003454:Cryptococcus / Q000187:drug effects*; D026121:Indole Alkaloids / Q000737:chemistry; D016018:Least-Squares Analysis; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry; D011806:Quinolinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015203:Reproducibility of Results; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014709:Vero Cells
D000935:Antifungal Agents; D026121:Indole Alkaloids; D011804:Quinolines; D011806:Quinolinium Compounds; D013438:Sulfhydryl Compounds; C024015:cryptolepine
Antifungal agents; CoMFA; Cryptolepine; Mycoses; Opportunistic infection; Substituted benzylthioquinolinium salts