Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies

Mohamed A. Ibrahim; Siva S. Panda; Alexander A. Oliferenko; Polina V. Oliferenko; Adel S. Girgis; Mohamed Elagawany; F. Zehra Küçükbay; Chandramukhi S. Panda; Girinath G. Pillai; Ahmed Samir; Kaido Tämm; C. Dennis Hall; Alan R. Katritzky

doi:10.1039/C5OB01400J

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies†

Mohamed A. Ibrahim,*^abc Siva S. Panda,*^ad Alexander A. Oliferenko,^a Polina V. Oliferenko,^a Adel S. Girgis,^e Mohamed Elagawany,^af F. Zehra Küçükbay,^ag Chandramukhi S. Panda,^a Girinath G. Pillai,

^ah Ahmed Samir,ⁱ Kaido Tämm,^h C. Dennis Hall^a and Alan R. Katritzky ‡^a

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* Corresponding authors

^a Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: drmmonem@yahoo.com, sspanda12@gmail.com
Fax: +1-352-392-9199
Tel: +1-352-870-9288

^b Department of Organic Chemistry, College of pharmacy, Misr University for Science and Technology, Al-Motamayez District, 6th of the October, P.O.Box: 77, Egypt

^c Department of Pharmaceutical Chemistry, Almaarefa Colleges for Science and Technology, Riyadh 11597, Kingdom of Saudi Arabia

^d Department of Chemistry & Physics, Georgia Reagents University, Augusta, GA 30912, USA

^e Pesticide Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt

^f Department of Pharmaceutical Chemistry, faculty of pharmacy, Damanhour University, Damanhour, Egypt

^g Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, İnönü University, 44280 Malatya, Turkey

^h Department of Chemistry, University of Tartu, 50411 Tartu, Estonia

ⁱ Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt

Abstract

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

Organic & Biomolecular Chemistry

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies†

Abstract

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Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies

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