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

• 2-chloro-3-(n-alkylamino)-1,4-naphthoquinones are synthesized and characterized.
• Single crystal X-ray structures reveal molecular association by hydrogen bondings.
• Molecular associations of aminonaphthoquinones are revealed by cyclic voltammetry.
• Antifungal activity is studied against C. tropicalis, C. albicans and C. herbarum.
• Methyl derivative shows promising antifungal activity.

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, 1H 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 Pca21 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.