δ-Carbolines and their ring-opened analogs: Synthesis and evaluation against fungal and bacterial opportunistic pathogens

Abstract

Previous studies have indicated that the δ-carboline (2) ring system derived from the natural product cryptolepine (1) may represent a pharmacophore for anti-infective activity. This paper describes the design and synthesis of a small library of substituted δ-carbolines and the evaluation of the antifungal and antibacterial activities. An evaluation of the anti-bacterial activity of a previously reported library of ring-opened analogs was also conducted to provide an opportunity to test the hypothesis that both group of compounds may have the same biological target. Results indicate that against a selected group of fungal pathogens, substituted δ-carbolinium analogs displayed higher potency and several fold lower cytotoxicity than cryptolepine the parent natural product. Both the δ-carbolinium compounds and their ring-opened analogs, exhibited equally high anti-bacterial activity against the selected pathogens and especially against the gram positive bacteria evaluated.

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

“…The CoMFA method used the partial-least squares (PLS) method to predict activity from the energy values at the grid points and the PLS method correlates the CoMFA fields with the activity values. 10,16 The models with cross-validated q 2 > 0.5 are indicative of a good predictive model. Cross-validation analysis was completed with SAMPLES turned-off and column filtering set to 2.0 kcal mol −1 to speed up the analysis.…”

“… a Compounds 3a-m were previously reported in references 10, 11 & 13. b Experimental pIC 50 . c Predicted IC 50 and pIC 50 from the CoMFA model; NC = Not cytotoxic at 10 μg/mL. * These were not included in the training set. …”

Synthesis and Optical Properties of Alkaloid Quindoline, Its Structural Analogues and Substituted δ‐Carbolines

“…In recent years, biological activity of δ‐carbolines (5 H ‐indolo[3,2 ‐b ]pyridines) has been actively studied . In 2011, high antifungal and antibacterial activity of iodine methylates of quaternary δ‐carbolinium salts was found.…”

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

“…[18] Much of these efforts have been reported. [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).…”