Synthesis, Molecular Docking, and Antimycotic Evaluation of Some 3-Acyl Imidazo[1,2-a]pyrimidines

Abstract

A series of 3-benzoyl imidazo[1,2-a]pyrimidines, obtained from N-heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species (Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC 6260), Candida kefyr, Candida krusei (ATCC 6358) and Candida tropicalis (MYA-3404)). To predict binding mode and energy, each compound was docked in the active site of the lanosterol 14α-demethylase enzyme (CYP51), essential for fungal growth of Candida species. Antimycotic activity was evaluated as the 50% minimum inhibitory concentration (MIC50) for the test compounds and two reference drugs, ketoconazole and fluconazole. All test compounds had a better binding energy (range: −6.11 to −9.43 kcal/mol) than that found for the reference drugs (range: 48.93 to −6.16 kcal/mol). In general, the test compounds showed greater inhibitory activity of yeast growth than the reference drugs. Compounds 4j and 4f were the most active, indicating an important role in biological activity for the benzene ring with electron-withdrawing substituents. These compounds show the best MIC50 against C. guilliermondii and C. glabrata, respectively. The current findings suggest that the 3-benzoyl imidazo[1,2-a]pyrimidine derivatives, herein synthesized by an accessible methodology, are potential antifungal drugs.

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing

“…The most frequent positions for such interactions are 310, 312, 372, 462, 463 and 468 for His, 379 and 381 for Arg, and 143 for Lys. In this research, as well as in previous studies, we corroborated that the following amino acids: Tyr118, Phe145, Ile231, Met306, His310, Thr311, Ser378, Val509 and Val511 are involved in the active site of CYP51 of C. albicans [80,83,86].…”

“…Ramachandran plots were also created for each model (Figures S69-S74), showing over 90% of the amino acid residues in the most favorable regions. Moreover, the models proved to be of good quality, as in previous studies by our group [80]. Docking simulations were carried out for the two series of 2-amino-3-cyano-4Hchromenes, 4a-o and 6a-h, at the active site of the CYP51 of Candida spp.…”

Targeted specific inhibition of bacterial and Candida species by mesoporous Ag/Sn–SnO2 composite nanoparticles: in silico and in vitro investigation

“…From our study it is found that a higher binding affinity acts between the Ag/Sn-SnO 2 NPs and lanosterol 1 4a-demethylase (À7.71 kcal mol À1 ) (Table 1) as compared to the earlier reported results for the uconazole (À4.44 kcal mol À1 ) or ketoconazole (32.55 kcal mol À1 ). 74 Further from this study it is evident that the binding of Ag/Sn-SnO 2 is possible with the active heme interacting pocket. It can be noted that the Lys143 of lanosterol 1 4a-demethylase is involved in ionic interaction with the heme ring and it affects the beta bulge.…”

Network Pharmacology and Experimental Assessment to Explore the Pharmacological Mechanism of Qimai Feiluoping Decoction Against Pulmonary Fibrosis

“…If the binding energy is less than 0, the compound (ligand) and protein (receptor) can bind spontaneously. If binding energy ≤ −1.2 kCal/mol, the ligand–receptor was considered stable ( Gomez-Garcia et al, 2018 ).…”