Multidrug-resistant fungal infections have become much
more common
in recent years, especially in immune-compromised patients. Therefore,
researchers and pharmaceutical professionals have focused on the development
of novel antifungal agents that can tackle the problem of resistance.
In continuation to this, a novel series of pyrazole-bearing pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives (4a–4o) have
been developed. These compounds have been screened against Candida albicans, Aspergillus niger, and Aspergillus clavatus. The synthesized
compounds were characterized by well-known spectroscopic techniques,
i.e., IR, 1H NMR, 13C NMR, and mass spectrometry. In vitro antifungal results revealed that compound 4n showed activity against C. albicans having MIC value of 200 μg/mL. To know the plausible mode
of action, the active derivatives were screened for anti-biofilm and
ergosterol biosynthesis inhibition activities. The compounds 4h, 4j, 4k, and 4n showed
greater ergosterol biosynthesis inhibition than the control DMSO.
To comprehend how molecules interact with the receptor, studies of
molecular docking of 4k and 4n have been
performed on the homology-modeled protein of β-tubulin. The
molecular docking revealed that the active compounds 4h, 4j, 4k, 4l, and 4n interacting with the active site amino acid of sterol 14-alpha demethylase
(PDB ID: 5v5z) indicate one of the possible modes of action of ergosterol inhibition
activity. The synthesized compounds 4c, 4e, 4h, 4i, 4j, 4k, 4l, and 4n inhibited biofilm formation
and possessed the potential for anti-biofilm activity. DFT-based quantum
mechanical calculations were carried out to optimize, predict, and
compare the vibration modes of the molecule 4a.