Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity

Abstract

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N′-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.

Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

“…Given the impressive physiochemical properties of the SF 5 unit, which include its high electronegativity (σ m = 0.61, σ p = 0.68; nearly equivalent to the NO 2 group: σ m = 0.73, σ p = 0.78) [30,31,32], high lipophilicity (π = 1.51; greater than that of the CF 3 group: π = 0.88 and the NO 2 group: π = −0.28) [32,33,34], and steric hindrance (nearly equivalent to that of the tert -butyl group) [34,35], the SF 5 -containing analogs of marketed drugs are attractive candidates in the future drug market (Figure 1b) [36,37,38,39,40,41]. More and more examples of biologically active SF 5 -containing drug candidates have been reported in recent years (Figure 1c) [35,38,39,40,41,42,43,44]. Extending our research to the design and synthesis of SF 5 -containing biologically attractive molecules [45,46,47,48,49,50,51,52,53,54,55,56,57] and a halogen bonding research program [58,59], we are interested in aryl iodides 1a – d consisting of SF 5 -group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular, 3,5-bis-SF 5 -iodobenzene ( 1d , Figure 1d).…”

Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics

“…In Table 2 , antibacterial and antifungal diarylureas are described. The work by Pujol et al [ 55 ] was devoted to diarylureas designed to overcome the toxicological effect of TCC due to the three chlorine atoms. One or more chlorine atoms of TCC were reduced and/or replaced by pentafluorosulfanyl groups, bioisosteres of the trifluoromethyl groups.…”

Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

“…[24][25][26][27][28][29] Given the impressive physiochemical properties of the SF5 unit, including its high electronegativity (σm = 0.61, σp = 0.68; nearly equivalent to the nitro (NO2) group), [30,31] high lipophilicity (π = 1.51; greater than the CF3 group) [32,33] and steric hindrance (nearly equivalent to the tert-butyl group), [34,35] the SF5-containing analogues of marketed drugs are attractive candidates in the future drugs market (Figure 1b). [36][37][38][39][40][41] More and more examples of biologically active SF5-contaning drug candidates have been reported in recent years ( Figure 1c). [34,[37][38][39][40][41] Extending our research to the design and synthesis of SF5-containing biologically attractive molecules [42][43][44][45][46][47][48][49][50][51][52][53][54] and a halogen bonding research program, [55,56] we are interested in aryl iodides 1a-d consisting of SF5-group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular, 3,5-bis-pentafluorosulfanyl iodobenzene 1d…”

“…[36][37][38][39][40][41] More and more examples of biologically active SF5-contaning drug candidates have been reported in recent years ( Figure 1c). [34,[37][38][39][40][41] Extending our research to the design and synthesis of SF5-containing biologically attractive molecules [42][43][44][45][46][47][48][49][50][51][52][53][54] and a halogen bonding research program, [55,56] we are interested in aryl iodides 1a-d consisting of SF5-group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular, 3,5-bis-pentafluorosulfanyl iodobenzene 1d (Figure 1d).…”