Analysis of stereoelectronic properties, mechanism of action and pharmacophore of synthetic indolo[2,1-b]quinazoline-6,12-dione derivatives in relation to antileishmanial activity using quantum chemical, cyclic voltammetry and 3-D-QSAR CATALYST procedures.
Several indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) derivatives exhibited remarkable activity at concentrations below 100 ng/mL when tested against in vitro Leishmania donovani amastigotes. The in vitro toxicity studies indicate that the compounds are fairly well tolerated in both macrophage and neuronal lines. An analysis based on qualitative and quantitative structure-activity relationship studies between in vitro antileishmanial activity and molecular electronic structure of 27 analogues of indolo[2,1-b]quinazoline-6,12-dione is presented here by using a combination of semi-empirical AM1 quantum chemical, cyclic voltammetry and a pharmacophore generation (CATALYST) methods. A modest to good correlation is observed between activity and a few calculated molecular properties such as molecular density, octanol-water partition coefficient, molecular orbital energies, and redox potentials. Electron transfer seems to be a plausible path in the mechanism of action of the compounds. A pharmacophore generated by using the 3-D QSAR of CATALYST produced a fairly accurate predictive model of antileishmanial activity of the tryptanthrins. The validity of the pharmacophore model extends to structurally different class of compounds that could open new frontiers for study. The carbonyl group of the five- and six-membered rings in the indolo[2,1-b]quinazoline-6,12-dione skeleton and the electron transfer ability to the carbonyl atom appear to be crucial for activity.
Bhattacharjee
Apurba K
AK
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, 20910, Silver Spring, MD, USA. apurba.bhattacharjee@na.amedd.army.mil
Skanchy
David J
DJ
Jennings
Barton
B
Hudson
Thomas H
TH
Brendle
James J
JJ
Werbovetz
Karl A
KA
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D003198:Computer Simulation; D004563:Electrochemistry; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D012984:Software; D013237:Stereoisomerism
D000981:Antiprotozoal Agents; D011799:Quinazolines