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Anti-fungal effects of novel N-(tert-butyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine derivative and it’s in-vitro, in-silico, and mode of action against Candida spp.

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Abstract

Imidazoles are a category of azole antifungals that encompass compounds such as ketoconazole, miconazole, esomeprazole, and clotrimazole. In contrast, the triazoles group, which includes fluconazole, voriconazole, and itraconazole, also plays a significant role. The rise of antibiotic resistance in fungal pathogens has evolved into a substantial global public health concern. In this study, two newly synthesized imidazo[1,2-a]pyridine derivative (Probe I and Probe II) molecules were investigated for its antimicrobial potency against of a panel of bacterial (Gram-positive and Gram-negative bacteria) and fungal pathogens. Among the different types of pathogens, we found that Probe II showed excellent antifungal activity against fungal pathogens, based on the preliminary screening the potent molecule further investigated against multidrug-resistance Candida sp. (n = 10) and compared with commercial molecules. In addition, in-silico molecular docking, its dynamics, absorption, distribution, metabolism, excretion and toxicity (ADMET) were analyzed. In this study, the small molecule (Probe II) displayed potent activity only against the Candida spp. including several multidrug-resistant Candida spp. Probe II exhibited minimum inhibitory concentration ranges from 4 to 16 µg/mL and minimum fungicidal concentration in the range 4‒32 µg/mL as the lowest concentration enough to eliminate the Candida spp. The selected molecules inhibit the formation of yeast to mold as well as ergosterol formation by the computational simulation against Sterol 14-alpha demethylase (CYP51) and inhibition of ergosterol biosynthesis by in-vitro model show that the Probe II completely inhibits the formation of ergosterol in yeast cells at 2× MIC. The ADMET analysis Probe II could be moderately toxic to the human being, though the in-vitro toxicity studies will help to understand the real-time toxic level. The novel compound Probe II, which was synthesized during the study, shows promise for development into a new generation of drug treatments aimed at addressing the emerging drug resistance in Candida sp.

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Data availability

The data that support the findings of this study are available on request from the corresponding author Dr. Manivannan Nandhagopal.

Abbreviations

ADMET:

Absorption, distribution, metabolism, excretion and toxicity

AIDS:

Acquired immune deficiency syndrome

MDR:

Multi-drug resistance

MIC:

Minimum inhibitory concentration

NA:

Not appeared

ND:

Not determined

NC:

Negative control

PC:

Positive control

ZOI:

Zone of inhibition

MFC:

Minimum fungicidal concentration

C1:

C. tropicalis (ATCC750)

C2:

C. albicans (KT315910)

C3:

C. tropicalis (KT315910)

C4:

C. albicans (KT315901)

C5:

C. albicans (KT831886)

C6:

Candida Sp. (KT831887)

C7:

C. dubliniensis (KT831888)

C8:

C. albicans (KT831889)

C9:

C. albicans (KT315909)

Probe I:

2-(3-(Tert-Butylamino)imidazo[1,2-a]pyridin-2-yl)phenol

Probe II:

N-(Tert-Butyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine

MD:

Molecular simulation

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

MHB:

Muller Hinton broth

MHA:

Muller Hinton agar

CLSI:

Clinical & Laboratory Standards Institute

PBS:

Phosphate buffer saline

PDB:

Protein data bank

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Acknowledgements

I sincerely acknowledge Dr. Jayapraksh priya BCMML, CAS in Botany, University of Madras for providing the fungal culture. I would like to acknowledge research scholar for BCMML, CAS for their help with data collection.

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Authors and Affiliations

  1. Bio-Control and Microbial Product Lab, Department of Microbiology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Thandalam, Chennai, 602105, India

    Manivannan Nandhagopal

  2. Organic and Bioorganic Chemistry Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai, 600020, India

    Ramanjaneyulu Mala

  3. Centre for Advanced Studies in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, 600 025, Tamil Nadu, India

    Kanagasabai Somarathinam

  4. Department of Chemistry, Vel Tech Rangarajan Dr, Sagunthala R&D Institute of Science and Technology, Avadi, Chennai, 600062, India

    Divya Dhakshinamurthy

  5. Biocontrol and Microbial Metabolites Lab, Centre for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India

    Mathivanan Narayanasamy & Priyadharshni Vijayan

  6. Department of Biochemistry, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Thandalam, Chennai, 602105, India

    Manimuthu Mani Shankar

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  1. Manivannan Nandhagopal
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Contributions

MN: design, research finding and experimental works; RM: molecule synthesis; KS: molecular docking and dynamics; DD: writing chemistry part; MN: framed experimental design and methodology; PV: study of inhibition of ergosterol biosynthesis; MMS: writing and correcting the manuscript.

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Correspondence to Manivannan Nandhagopal.

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Nandhagopal, M., Mala, R., Somarathinam, K. et al. Anti-fungal effects of novel N-(tert-butyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine derivative and it’s in-vitro, in-silico, and mode of action against Candida spp.. Arch Microbiol 206, 186 (2024). https://doi.org/10.1007/s00203-023-03780-w

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