Abstract
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.
Highlights
The pyrrole carboxamide skeleton is an important and unique class of heterocyclic compounds which has yet to be well explored [1,2]
The search for precise and robust synthetic routes as part of our continued efforts to develop potent antibacterial compounds motivated us to develop a facile synthesis of these bioactive scaffold- containing analogues in one-pot protocols
We envisioned that parallel syntheses of 2,4-dimethylpyrrole carboxamide and carbohydrazide derivatives having various substituents on aryl adducts could be achieved in higher yields
Summary
The pyrrole carboxamide skeleton is an important and unique class of heterocyclic compounds which has yet to be well explored [1,2]. Numerous marine-derived novel compounds [3] containing an integral carboxamide motif as highlighted in Figure 1 exhibit varied biological activities that are important for potential drug development, e.g., dispyrin, a bromopyrrole alkaloid (antagonist of α2A , H2 and H3 histamine receptors), dispacamide-A (anti-histaminic), sceptrin (antiviral), agelastatin-A, yatakemycin, (antitumor), storniamide-A (antibacterial), hymenialdisine (kinase inhibitor), distamycin and netropsin (DNA minor groove binders) [4,5,6,7,8,9,10,11]. Synthetic pyrrole carboxamides show a wide range of pharmacological properties, including tyrosine kinase inhibition. They bind to dopamine-D2 -like receptors and modulate protein kinase activity.
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