Abstract
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.
Highlights
Bacterial drug resistance is one of the major problems in public health worldwide.Reports from different health organizations make claims that antibacterial resistance is responsible for more than 35,000 deaths in the United States and about 33,000 deaths in European Union, annually [1,2]
We evaluate the antimicrobial activity of quaternary derivatives of cinchonidine and cinchonine by using disc diffusion and broth microdilution assay against a representative panel of Gram-positive and Gram-negative bacteria
A series of differently substituted quaternary ammonium salts of CDs and their corresponding quasi-enantiomeric CNs were synthesized by reaction of commercially available cinchonidine or cinchonine and alkyl or arylalkyl halides in refluxing toluene by published procedures [17]
Summary
Bacterial drug resistance is one of the major problems in public health worldwide.Reports from different health organizations make claims that antibacterial resistance is responsible for more than 35,000 deaths in the United States and about 33,000 deaths in European Union, annually [1,2]. A lot of effort has been put into the research and development of antibacterial agents against emerging new bacterial strains. Cinchona alkaloids are natural products isolated from the bark of the Cinchona tree and the most known are quinine (Q), quinidine (QD), cinchonine (CN), and cinchonidine (CD). The structure of these alkaloids consists of a bulky quinuclidine ring with a vinyl side chain, Antibiotics 2021, 10, x FOR PEER REVIEW an aromatic quinolineanrdinthge,maonstdknaowhnyadreroquxiynilneg(rQo)u, qpuinaitdiCne9(.QTDh),eciynchhoanvinee fi(CvNe), canhdircainlchcoennidtienres (N1, C3, C4, C8, and C9) an(CdDt).wThoe ostfrutchtuerme o,f Cth8eseaanlkdalCoid9s, ccoannsishtsaovf ea bduilkffyeqrueinutcalidbisnoe lruintgewciothnafivginuylration in Q/QD and CN/CsDidepchaaiirns, ,ansoarotmhaetsicequdiniaolsinteerriengo,manedrashaydrreoxoyfl tgeronupcaatlCle9d.
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