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New Route to the Synthesis of Novel Pyrazolo[1,5-a]pyrimidines and Evaluation of their Antimicrobial Activity as RNA Polymerase Inhibitors.

Aims The current study aimed to synthesize novel pyrazolo[1,5-a]pyrimidines based on 5-aminopyrazoles 3, evaluate their antimicrobial activity, and study the minimum inhibitory concentration (MIC) for the most active compounds. In addition, molecular docking studies and RNA polymerase inhibitory activity were determined. Background Starting with our previously reported 5-aminopyrazoles 3, a number of novel pyrazolo[1,5-a]pyrimidines were synthesized. Due to the similarity of pyrazolopyrimidine derivatives with the purine systems, pyrazolopyrimidines are important in many different biological applications, most notably as anti-tumor, anti-bacterial, and hepatitis C virus inhibitors. The pharmaceutical applications of the pyrazolopyrimidine derivatives were explained in several approved drugs like Indiplon, Zaloplan, and Ocinaplon. Objective To prepare a novel antimicrobial agent, namely pyrazolo[1,5-a]pyrimidine, reveal their structures using different spectral data, evaluate the minimum inhibitory concentration (MIC) for the most active compounds, and determine both the molecular docking and the RNA polymerase inhibitory activity. Methods A number of different pyrazolopyrimidines namely 2-(phenylamino)-6,11-dihydrobenzo[g]pyrazolo[1,5-a]quinazoline-3-carboxamides (5a-c), (E)-5,7-dimethyl-2-(phenylamino)-6-(phenyldiazenyl)pyrazolo-[1,5-a]pyrimidine-3-carboxamides (7a-c), 7-amino-2-(phenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamides (11a-f), 7-amino-2-(phenylamino)-5-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxamides (14-f) and ethyl 7-amino-3-carbamoyl-2-(phenylamino)-5-(4-pyridyl)pyrazolo-[1,5-a]pyrimidine-6-carboxylate derivatives (14g-i) were synthesized through the reaction of 5-aminopyrazoles 3 with a variety of chemical reagents. On the other hand, the evaluation of the antimicrobial activity for all the prepared compounds was screened through different strain as Gram-positive bacteria such as staphylococcus aureus and Streptococcus mutans, and Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and klebsiella. The antifungal activity was determined by Candids Albicans fungal strain, and the MIC of the most active compounds was measured. The molecular docking was recorded, and the RNA polymerase inhibitory activity was estimated for the high docking score compounds. Results Compounds 5a, 5b, 5c, 7a, 7b, 7c, 11d, 14b and 14h were the most active compounds against some of the bacterial and fungal tested strains. MIC was determined for the most active tested compounds. As an antimicrobial agent, compound 7b was the most potent, with a high docking score and RNA polymerase inhibitory activity (IC50= 0.213 µg/ml) compared to Rifampicin (IC50= 0.244 µg/ml). The reactivity of the latter compound was attributed to the presence of 4-Br-C6H4 moiety. The results demonstrated that docking studies on the most active compounds in the RNA polymerase active site were consistent with in vitro assays . Conclusion The resultant novel bioactive pyrazolo[1,5-a]pyrimidine derivatives were synthesized based on 5-aminopyrazole derivatives 3. The current study evaluated the antimicrobial activity for all the prepared compounds, followed by the determination of the MIC for the most potent active compounds. The molecular docking study was performed, and it was appropriate with the in vitro activity. The RNA polymerase inhibitory activity was assessed for the most active antimicrobial compounds with a high docking score (7b, 7c, 14a, 14b, 14e, 14i). Compound 7b was the most potent compound inhibiting RNA polymerase enzyme compared to the reference drug Rifampicin. The novel prepared heterocyclic systems have remarkable importance in the whole fields, particularly in biological and pharmaceutical applications.