Efficient Synthesis and Antimicrobial Activities of Long Alkyl Chain Trifluoromethyl1H-pyrazol-1-(thio)carboxamides and Trifluoromethyl-1H-pyrazol-1-yl-thiazoles

Débora L De Mello ,Sidnei Moura,Roberto C.v Santos ,Darlene C Flores ,Juliana L Malavolta ,Leonardo Quintana Soares Lopes ,Alex F C Flores

doi:10.21577/0103-5053.20200241

Abstract

The synthesis of 3-alkyl-5-trifluoromethyl-1H-pyrazole-1-carboxamides, 3-alkyl5-trifluoromethyl-1H-pyrazole-1-thiocarboxamides, and 2-(3-alkyl-5-trifluoromethyl-1H-pyrazol1-yl)-thiazoles derivatives are reported. [3 + 2] cyclocondensations for a series of long alkyl chain 1,1,1-trifluoro-4-methoxyalk-3-en-2-ones and semicarbazide or thiosemicarbazide were carried out in ethanol, an eco-friendly medium. The series of trifluoromethyl-1H-pyrazol-1-ylthiocarboxamide following a [3 + 2] cyclocondensation with 2-bromoacetophenone were converted into two series of 2-(3-alkyl-5-trifluoromethyl-1H-pyrazol-1-yl)-thiazoles. Good yields (69-96%) of the isolated products were obtained. The structures of the new long alkyl chain 1H-pyrazoles and 2-(1H-pyrazol-1-yl)thiazoles were characterized using 1 H, 13C, and 19F nuclear magnetic resonance (NMR) spectroscopy and electrospray ionization tandem mass spectrometric (ESI MS/MS) data. Moreover, some of the products were evaluated for their antimicrobial activity against Gram-negative Escherichia coli American Type Culture Collection (ATCC) 35218, Salmonella enteritidis ATCC 13076, and Pseudomonas aeruginosa ATCC 15692; and Gram-positive Staphylococcus aureus ATCC 6538, methicillin resistant Staphylococcus aureus (MRSA clinical isolate), Streptococcus sp. (clinical isolate), and Candida albicans ATCC 14053 and Candida krusei ATCC 6258 fungi. All the tested 1H-pyrazoles exhibited antibacterial and antifungal activities at the tested concentrations. The compounds from series 4 were found to be powerful against MRSA.

Highlights

Bacterial and fungal diseases affect millions of human worldwide every day
As reported earlier for 3-alkyl-5-hydroxy-5-trichloromethyl-4,5-dihydro1H‐pyrazole-1-carboxamide and 1-thiocarboxamide derivatives,15,16 attempts at the aromatization of 2d with sulfuric acid led to the formation of only a tautomeric compound (6d), which was obtained as a yellowish wax at an 80% yield, demonstrating that in this medium the elimination of carbamic acid occurs for these trifluoromethyl derivatives (Scheme 1)
The results showed that the unbranched C6-C13 alkyl chain in trifluoromethyl-1H-pyrazol-1-(thio)carboxamides [2, 3] and trifluoromethyl-1H-pyrazol-1-yl-thiazoles [4, 5] was not very relevant to antimicrobial activity

Summary

Introduction

Bacterial and fungal diseases affect millions of human worldwide every day. Several million doses of antibiotics are prescribed annually for these infections, contributing to the current problem of increased antibiotic resistance. The 1,1,1-trifluoro-4-methoxy-3-alken-2-ones were obtained as described earlier.13 Following the conventional route to CX3-containing 1H-pyrazole,15 the synthesis of the 3-alkyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro1H‐pyrazole-1-carboxamides was performed by reacting semicarbazide hydrochloride, pyridine, and 1,1,1-trifluoro4-methoxy-3-tridecen-2-one (1d) in H2O at reflux for 16 h to give 65-76% yields, as outlined in Scheme 1. When the reaction of 3d with 2-bromoacetophenone was conducted at 30 °C for 16 h, 3-nonyl-1-(4-phenylthiazol-2-yl)-5-hydroxy5-(trifluoromethyl)-4,5-dihydro-1H‐pyrazole (4d) was obtained at a good yield of 86%, without any indication of another product being formed.

Results

Conclusion