title: Synthesis of amino acid appended indoles: appreciable anti-fungal activity and inhibition of ergosterol biosynthesis as their probable mode of action.
abstract: Rationally designed compounds consisting of mono- and di-peptide appendages on bis-indole template were synthesized in appreciable yield. Some of these compounds exhibited significant antifungal activities against Candida albicans with their MIC80 in μg/ml range. However, when used in combination with azoles, the antifungal activities of the azoles were considerably enhanced. The growth inhibition appeared to be specific to the fungal cells and mammalian cells were not affected by these compounds. It is shown that these compounds lower ergosterol levels in the fungal cells and probably act by targeting lanosterol 14α-demethylase, a key enzyme in the sterol biosynthetic pathway of C. albicans. The compounds do not appear to directly act on the fungal cell wall. Hence, the sensitivity of the fungal cells to these compounds cannot be attributed to cell wall damage and consequent accumulation of the compounds in the cell, though defects in cell wall due to defective sterol biosynthesis cannot be completely ruled out.
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.lastname: Pooja
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Parteek
authors.initials: P
authors.lastname: Prasher
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: palwinder_singh_2000@yahoo.com.
authors.forename: Palwinder
authors.initials: P
authors.lastname: Singh
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Pawar
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Kunwar Somesh
authors.initials: KS
authors.lastname: Vikramdeo
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Neelima
authors.initials: N
authors.lastname: Mondal
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: sskomath@yahoo.com.
authors.forename: Sneha Sudha
authors.initials: SS
authors.lastname: Komath
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020134:Catalytic Domain; D002473:Cell Wall / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004875:Ergosterol / Q000096:biosynthesis*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000935:Antifungal Agents; D007211:Indoles; C030374:indole; D058886:Sterol 14-Demethylase; D004875:Ergosterol
keywords: Amino acid; Anti-fungal; Indole; Lanosterol 14α-demethylase