Molecular structures and biological evaluation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone derivatives as potent antifungal agents

Abstract Derivatives of 2-chloro-3-( n -alkylamino)-1,4-naphthoquinone { n -alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} have been synthesized and characterized by elemental analysis, FT-IR, 1 H NMR, UV–visible spectroscopy, LC-MS and single crystal X-ray diffraction studies. Antifungal activity of L-1 to L-4 has been evaluated against Candida tropicalis , Candida albicans and Cladosporium herbarum . The intramolecular hydrogen bonding affects the N–H vibrational frequency in L-2 (3273 cm −1 ). The single crystal X-ray structure reveal that L-1 and L-3 crystallizes in triclinic P -1, whereas L-2 crystallizes in orthorhombic Pca 2 1 space group. An extensive intra and intermolecular hydrogen bonding interactions were observed in L-1 to L-3 which leads to molecular association. Intramolecular N–H⋯O hydrogen bonding were observed in L-1 to L-3. Moreover π – π stacking interactions were observed between the quinonoid rings of L-1 and L-3, however no such interactions were observed in L-2. An electrochemical study showed molecular association of L-1 to L-4 in DMSO solution. Compounds L-1 to L-4 were found to be potent antifungal agents against all the three strains, especially against C . tropicalis . Amongst these promising antifungal candidates, L-1 showed better activity compared to the clinically administered antifungal drug Amphotericin B and Nitrofurantoin with MIC = 1.25 μg ml −1 and MIC = 0.025 μg ml −1 respectively against C . albicans . Structure and activity relationship (SAR) study suggest a Log  P value of ∼2.0 and the cyclic voltammetry studies reveals additional chemical processes for L-1, which exhibits maximum activity against all fungal strains.