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Article

Antimicrobial Activity of Quasi-Enantiomeric Cinchona Alkaloid Derivatives and Prediction Model Developed by Machine Learning

1
Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
2
Faculty of Science, University of Split, 21000 Split, Croatia
3
Ruđer Bošković Institute, 10000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Academic Editor: Yuji Morita
Antibiotics 2021, 10(6), 659; https://doi.org/10.3390/antibiotics10060659
Received: 7 May 2021 / Revised: 24 May 2021 / Accepted: 27 May 2021 / Published: 31 May 2021
(This article belongs to the Special Issue Antimicrobial Resistance in Gram-Negative Bacteria, 2nd Edition)
Bacterial infections that do not respond to current treatments are increasing, thus there is a need for the development of new antibiotics. Series of 20 N-substituted quaternary salts of cinchonidine (CD) and their quasi-enantiomer cinchonine (CN) were prepared and their antimicrobial activity was assessed against a diverse panel of Gram-positive and Gram-negative bacteria. All tested compounds showed good antimicrobial potential (minimum inhibitory concentration (MIC) values 1.56 to 125.00 μg/mL), proved to be nontoxic to different human cell lines, and did not influence the production of reactive oxygen species (ROS). Seven compounds showed very strong bioactivity against some of the tested Gram-negative bacteria (MIC for E. coli and K. pneumoniae 6.25 μg/mL; MIC for P. aeruginosa 1.56 μg/mL). To establish a connection between antimicrobial data and potential energy surfaces (PES) of the compounds, activity/PES models using principal components of the disc diffusion assay and MIC and data towards PES data were built. An extensive machine learning procedure for the generation and cross-validation of multivariate linear regression models with a linear combination of original variables as well as their higher-order polynomial terms was performed. The best possible models with predicted R2(CD derivatives) = 0.9979 and R2(CN derivatives) = 0.9873 were established and presented. This activity/PES model can be used for accurate prediction of activities for new compounds based solely on their potential energy surfaces, which will enable wider screening and guided search for new potential leads. Based on the obtained results, N-quaternary derivatives of Cinchona alkaloids proved to be an excellent scaffold for further optimization of novel antibiotic species. View Full-Text
Keywords: quaternary cinchonidines; quaternary cinchonines; antimicrobial activity; cytotoxicity; ROS; activity/PES model; machine learning quaternary cinchonidines; quaternary cinchonines; antimicrobial activity; cytotoxicity; ROS; activity/PES model; machine learning
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MDPI and ACS Style

Ramić, A.; Skočibušić, M.; Odžak, R.; Čipak Gašparović, A.; Milković, L.; Mikelić, A.; Sović, K.; Primožič, I.; Hrenar, T. Antimicrobial Activity of Quasi-Enantiomeric Cinchona Alkaloid Derivatives and Prediction Model Developed by Machine Learning. Antibiotics 2021, 10, 659. https://doi.org/10.3390/antibiotics10060659

AMA Style

Ramić A, Skočibušić M, Odžak R, Čipak Gašparović A, Milković L, Mikelić A, Sović K, Primožič I, Hrenar T. Antimicrobial Activity of Quasi-Enantiomeric Cinchona Alkaloid Derivatives and Prediction Model Developed by Machine Learning. Antibiotics. 2021; 10(6):659. https://doi.org/10.3390/antibiotics10060659

Chicago/Turabian Style

Ramić, Alma, Mirjana Skočibušić, Renata Odžak, Ana Čipak Gašparović, Lidija Milković, Ana Mikelić, Karlo Sović, Ines Primožič, and Tomica Hrenar. 2021. "Antimicrobial Activity of Quasi-Enantiomeric Cinchona Alkaloid Derivatives and Prediction Model Developed by Machine Learning" Antibiotics 10, no. 6: 659. https://doi.org/10.3390/antibiotics10060659

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