Molecular Docking Studies of Novel Aminopyrimidines as Potent Antifungal Agents (original) (raw)
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Bioorganic & Medicinal Chemistry, 2009
In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.
Molecular Docking and In-Vitro Antimicrobial Activty of Some Novel Aminopyrimidine Derivatives
2021
The emergence of drug-resistant microbes left us with a great need for new antimicrobial agents. Aminopyrimidines, with their wide range of biological activities, are good candidates in this respect. The derivatives of the title scaffold had proven to possess great potential, inhibiting and cidal activity of microbes even at concentrations below 1 μg ml. The substitution pattern of these aminopyrimidines often includes hydroxy groups, halogens or other heteroaromic rings, In this article, we aim to report the molecular docking and in-vitro antimicrobial activity of our novel derivatives AD (1-6). Among all six novel derivatives, two of them AD3 & AD4 were showing significant antimicrobial activity against both the gram positive and gram negative bacteria.
Organic communications, 2022
Pyrimido[4,5-d]pyrimidine conveys antimicrobial activity against various micro pathogens having functionalized properties. As a result, this study has designed to illustrate the antibacterial, antifungal, and antiviral properties of pyrimido[4,5-d]pyrimidine. First of all, these structures have been optimized from the characterization of synthesis for calculating chemical descriptors by DFT. Next, the auto docking and target docking against 12 proteins, such as Pseudomonas aeruginosa (2Y0H), Bacillus cereus (1AH7), Escherichia coli (6DR3), Shigella dysenteriae (3FHH) Salmonella typhi (3FHU), Aspergillus niger (1ACZ), Aspergillus flavus (1XY3), Rhizomucor miehei (4WTP), Candida auris (6U8J), three proteins of SARS-CoV-2 (7T9J, 7T9L, and 7TB4) were performed for the determination of binding sites and binding affinity. One FDA approved drug (Ampicillin) has docked against 12 proteins while the Bacillus cereus (Bacteria), Aspergillus flavus (Fungus), and SARS-CoV-2, 7T9L (Omicron) are obtained the best binding affinity after docking. The most common residues are the PHE-66, ARG-176 and VAL-124 for Bacillus cereus, Aspergillus flavus and SARS-CoV-2, Omicron (7T9L), respectively, as they blocked the active sites by the ligands as inhibitors. It is revealed that this study contained both auto docking and target docking whereas the binding affinity of auto docking is that the binding affinity for auto docking is higher than target docking. Finally, among the nine compounds, three compounds show outstanding results against bacteria, fungus and virus. At last, molecular dynamics were performed to check the stability and validation of the docked complex and quantum calculations obtained the molecular properties, as well as ADMET, pharmacokinetics, Lipinski Rule and QSAR data.
BMC Chemistry, 2019
Pyrimidine nucleus is a significant pharmacophore that exhibited excellent pharmacological activities. A series of pyrimidine scaffolds was synthesized and its chemical structures were confirmed by physicochemical and spectral analysis. The synthesized compounds were evaluated for their antimicrobial potential towards Gram positive and negative bacteria as well as fungal species. They were also assessed for their anticancer activity toward a human colorectal carcinoma cell line (HCT116). Whilst results of antimicrobial potential revealed that compounds Ax2, Ax3, Ax8 and Ax14 exhibited better activity against tested microorganisms, the results of antiproliferative activity indicated that compounds Ax7 and Ax10 showed excellent activity against HCT116. Further, the molecular docking of pyrimidine derivatives Ax1, Ax9 and Ax10 with CDK8 (PDB id: 5FGK) protein indicated that moderate to better docking results within the binding pocket. Compounds Ax8 and Ax10 having significant antimicrobial and anticancer activities may be selected as lead compounds for the development of novel antimicrobial and anticancer agent, respectively.
Synthesis, Molecular Docking, and Antimycotic Evaluation of Some 3-Acyl Imidazo[1,2-a]pyrimidines
Molecules (Basel, Switzerland), 2018
A series of 3-benzoyl imidazo[1,2-]pyrimidines, obtained from -heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven species ( (ATCC 10231), (CD36), (CBS138), (ATCC 6260), , (ATCC 6358) and (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 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 and were the most active, indicating an important role in biological activity for the benzene ring with electron-withdrawing substit...
MOLECULAR DOCKING STUDIES OF THIAZOLOPYRIMIDINE DERIVATIVES AS ANTIMICROBIAL AGENTS
Journal of Advanced Scientific Research, 2021
Antimicrobial agents are essential drugs for the health of humans and animals as they cure infectious diseases produced by several contagious strains (bacteria, fungi, parasites, and viruses). Antibiotics efficacy is restricted by an increased number of antibiotic-resistant bacteria. Computational chemistry is crucial in the development of novel potential therapeutics. In this study, the objective was to integrate the two separately bioactive molecules, i.e., thiazoles and pyrimidines into one molecule to produce compounds with better pharmacological activity. Various thiazolo-pyrimidine derivatives were planned through a suitable synthetic scheme and were docked on DNA gyrase subunit B and dihydrofolate reductase, which are established targets for microbial infection. The results were studied and the findings were compared to two known medications as well as potential inhibitors. The result recognizes few thiazolo-pyrimidine derivatives with increased binding efficiency leading to enhanced potency.
Bioorganic & Medicinal Chemistry, 2019
A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC 50 of 1.88 µM against reference standard suramin (IC 50 ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.
Molecules
The article describes the use of facile one-pot, high-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamides 3a-m and carbohydrazide analogues 5a-l as potential antifungal and antimicrobial agents. The structural identity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compounds 5h, 5i and 5j were found to be the most potent against Aspergillus fumigatus, with MIC values of 0.039 mg/mL. The compound 5f bearing a 2, 6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with a MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking with the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron-related deleterious side effects observed with many existing antifungal compounds.
Molecules
A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. Background: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. Methods: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a–d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. Results: T...
2019
New fused pyrido-pyrimidine and naphthyridine cycles were synthesized and characterized using spectral analysis. Initially, 2-cyano-N-(1-phenylethylidene) acetohydrazide (2) was prepared from the reaction of cyanoacetic acid hydrazide (1) with acetophenone then cyclized to 4,6-diamino-2-oxo-1-((1- phenylethylidene)amino)-1,2-dihy-dropyridine-3-carbonitrile (3) by the action of malononitrile and triethyl amine in dioxin. Fused pyridopyrimidine cycles (4-6) were obtained from the reaction of compound 3 with formic acid, glacial acetic acid and propionic acid, respectively in the presence of POCl3 as a catalyst. The novel cycles (7-9) were synthesized from the cyclization reaction of compound 3 with benzoyl chloride, phenylisocyanate and phenylisothiocyanate in presence of pyridine. Naphthyridine cycles (10-13) were obtained by cyclization of compound 3 with some of aliphatic ketones namely; acetone, cyclohexanone, 2-butanone and 4-methyl-2-pentanone, respectively in presence of FeCl3 as catalyst. The antimicrobial activity of the synthesized derivatives was evaluated against several bacterial species as well as candida albicans. Docking study was also achieved to explore the binding affinity of the potent discovered hit (9) inside the binding pocket of glucosamine-6-phosphate synthase, a target enzyme for the antimicrobial agents.