Synthesis, Structure Optimization and Antifungal Screening of Novel Tetrazole Ring Bearing Acyl-Hydrazones

Maqsood Ahmad Malik,Manzoor A Malik,Shaeel Ahmed Al-Thabaiti

doi:10.3390/ijms130910880

Maqsood Ahmad Malik, Manzoor A Malik + Show 1 more

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https://doi.org/10.3390/ijms130910880

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Abstract

Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In an attempt to find novel azole antifungal agents with improved activity, a series of tetrazole ring bearing acylhydrazone derivatives were synthesized and screened for their in vitro antifungal activity. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and determination of the levels of ergosterol, a fungal-specific sterol. Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane. Target compounds also caused a considerable reduction in the amount of ergosterol. The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

Highlights

Candida albicans is an opportunistic and often deadly pathogen that invades host tissues, undergoes a dimorphic shift, and grows as a fungal mass in the kidney, heart or brain
Our results showed that propidium iodide (PI) penetrates over 80% of the yeast cells when treated with 4× Minimum Inhibitory Concentration (MIC) of compound TH3 and TH4, indicating that the structure of the cell membrane was disrupted by these test compounds to a large extent
The present study achieved the excellent synthesis of a novel series of tetrazole ring bearing acyl hydrazone derivatives (TH1–TH10)

Summary

Introduction

Candida albicans is an opportunistic and often deadly pathogen that invades host tissues, undergoes a dimorphic shift, and grows as a fungal mass in the kidney, heart or brain. It is the fourth leading cause of hospital-acquired infection in the United States and over 95% of AIDS patients suffer from infections by C. albicans [1,2]. Polyenes (amphotericin B and nystatin) cause serious host toxicity [4] whereas azoles are fungistatic and their prolonged use contributes to the development of drug resistance in C. albicans and other species [5,6]. Because of all these striking problems, there is a pressing need to develop novel antifungal drugs with higher efficiency, broader spectrum, improved pharmacodynamic profiles and lower toxicity

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