Broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects.
Various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. Staphyllococcus aureus-ATCC 7000699, MRSA and S. aureus-ATCC 29213 (Quality Control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had MIC50of 0.4μg/mL (cf. Gentamicin=0.78μg/mL). CLogP value, optimally in the range of 2.5-3.5, appeared to contribute more to the activity than the steric and electronic effects of groups attached at nitrogen. By and large, their anti-fungal activities also followed a similar trend with respect to the structure and CLogP values. The best potency of IC50=0.1μg/mL was shown by N-benzyl derivative (1.7) against Aspergillus fumigatus; it was also potent against Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, and Candida parapsilosis with IC50values ranging from 0.4 to 1.3μg/mL. Preliminary studies also showed that this class of compounds have the ability to target malaria parasite with IC50values in low micromolar range, and improvement of selectivity is possible through structure optimization.
Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600036, India.
P
P
Gopinath
Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
R K
RK
Yadav
Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
P K
PK
Shukla
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
K
K
Srivastava
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
S K
SK
Puri
Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600036, India. Electronic address: mkm@iitm.ac.in.
K M
KM
Muraleedharan
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D005658:Fungi / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000935:Antifungal Agents; D013844:Thiazoles; C015699:1,2-benzisothiazoline-3-one
Anti-infective agents; Antibacterial; Antifungal; Antimalarial; Benzisothiazolones