Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Abstract

A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

“…Anilides of 3-(trifluoromethyl)cinnamic acid (series 1 ) and 4-(trifluoromethyl)cinnamic acid (series 2 ) were synthesized according to Scheme 1 as described previously by Strharsky et al [ 28 ]. Briefly, acid dissolved in dry chlorobenzene in the presence of phosphorus trichloride and the appropriate aniline in a microwave reactor yielded targeted N -arylcinnamamides (see Table 1 ).…”

“…Based on the previous results of our compounds, where lipophilicity was shown to significantly affect biological activities [ 26 , 27 , 28 ], lipophilicities were also experimentally determined for all the investigated compounds by RP-HPLC, as the logarithm of the capacity factor k and the logarithms of the distribution coefficients D at physiological pH values of 6.5 and 7.4 [ 34 , 35 ]. It is evident from the graphs in Figure 1 that the correlation coefficients of the dependences of log k /log D 6.5 /log D 7.4 have a value of r = 0.999 (n = 32), which means that the investigated compounds behave insignificantly differently in aqueous media with different pH.…”

“…In addition, only 4c – f were active against M. smegmatis and M. marinum (average MIC ~4.1 µM) safe models mimicking M. tuberculosis . All the effective compounds showed bactericidal activity [ 28 , 56 ]. Of the compounds discussed in this paper, the majority of active derivatives were from series 1 (R 1 = 3-CF 3 ), although two of the effective derivatives from series 2 were more potent.…”

“…Experimental determination of lipophilicity values (log k , log D 6.5 , and log D 7.4 ) was performed under the same conditions and on the same device as described by Strharsky et al [ 28 ]. The log k values of individual compounds are shown in Table 1 .…”

“…A number of cinnamic acid anilides were prepared and tested [ 26 , 27 ]. Subsequent chlorination of the benzene ring gave much more potent compounds [ 28 ], and as sufficient lipophilicity was found to be essential for the efficacy of these compounds, new series were prepared where the chlorine atoms were replaced by a trifluoromethyl group either in the meta - or para -position of the cinnamic acid benzene ring. Moieties with electron-withdrawing properties were also chosen as substituents on the anilide ring.…”