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Bioorganic & Medicinal Chemistry
Volume 13, Issue 23, 1 December 2005, Pages 6289-6308
 
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doi:10.1016/j.bmc.2005.08.011    How to Cite or Link Using DOI (Opens New Window)
Copyright © 2005 Elsevier Ltd All rights reserved.

N-Methylthio β-lactam antibacterials: Effects of the C3/C4 ring substituents on anti-MRSA activity

Edward Turosa, Corresponding Author Contact Information, E-mail The Corresponding Author, Cristina Coatesa, Jeung-Yeop Shima, Yang Wanga, J. Michelle Lesliea, Timothy E. Longa, G. Suresh Kumar Reddya, Alex Ortiza, †, Marci Culbreatha, †, Sonja Dickeyb, Daniel V. Limb, Eduardo Alonsoc and Javier Gonzalezc

aDepartment of Chemistry, 4202 East Fowler Avenue, SCA 400, University of South Florida, Tampa, FL 33620, USA bDepartment of Biology, University of South Florida, Tampa, FL 33620, USA cDepartamento de Quimica Organica, Universidad de Oviedo, 37006 Oviedo, Spain

Received 7 December 2004; 
revised 31 March 2005; 
accepted 31 March 2005. 
Available online 26 September 2005.

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Abstract

N-Thiolated β-lactams are a new family of antibacterials that inhibit the growth of Staphylococcus bacteria. Unlike other β-lactam drugs, these compounds retain their full antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains and operate through a different mode of action. The structural features, which give these lactams their biological activity, have not yet been completely defined. Earlier efforts in our laboratory established that the N-organothio substituent is essential for antimicrobial activity while other groups at C3 and C4 on the lactam ring play a more subtle role. In this present study, we investigate these effects by varying the polar and steric nature of the ring substituents at these two centers. From the data presented herein, it appears that there is a need to balance the lipophilic character of the C3/C4 groups to obtain an optimal anti-MRSA activity. The structure–bioactivity profiles more closely relate to the compound’s ability to penetrate the bacterial cell membrane to sites of action within the cytoplasm rather than to any specific non-bonding interactions with a biological target. Based on these results, a model for the compounds’ mode of action is presented.

Graphical abstract

This report describes a study of the antibacterial properties of N-methylthio β-lactams 1 as a function of the C3/C4 ring substituents R1, R2, R3, and R4.

Full-size image

Keywords: N-Thiolated β-lactams; MRSA; SAR; Antibiotics

Article Outline

1. Introduction
2. Results and discussion
2.1. Synthesis and evaluation of C3-substituted analogues
2.2. Microbiological testing of C3/C4-substituted lactams
3. Conclusions
4. Experimental
4.1. Synthesis of 2-chlorophenyl-N-(4-methoxyphenyl)-imine (21a)
4.2. N-(4-Methoxyphenyl)phenyl-imine (21b)
4.3. Synthesis of (±)-(3R,4S)-3-acetoxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)azetidin-2-one (22a)
4.4. (±)-(3R,4S)-3-Acetoxy-N-(4-methoxyphenyl)-4-phenyl-azetidin-2-one (22b)
4.5. Synthesis of (±)-(3R,4S)-4-(2-chlorophenyl)-3-hydroxy-N-(4-methoxyphenyl)azetidin-2-one (23)
4.6. (±)-(3R,4S)-3-Hydroxy-4-phenyl-N-(4-methoxyphenyl)-azetidin-2-one (34)
4.7. Synthesis of (±)-(3S,4S)-3-chloro-4-(2-chlorophenyl)-N-(4-methoxyphenyl)azetidin-2-one (24a)
4.8. Synthesis of (±)-(3S,4S)-4-(2-chlorophenyl)-3-iodo-N-(4-methoxy-phenyl)azetidin-2-one (24b)
4.9. (±)-(3S,4S)-3-Azido-N-(4-methoxyphenyl)azetidin-2-one (24c)
4.10. Synthesis of (±)-(4S)-4-(2-chlorophenyl)-N-(4-methoxyphenyl)-3-oxoazetidin-2-one (27)
4.11. Synthesis of (±)-(3S,4S)-4-(2-chlorophenyl)-3-cyclo-pentylamino-N-(4-methoxyphenyl)azetidin-2-one (28a)
4.12. (±)-(3S,4S)-3-Benzylamino-4-(2-chlorophenyl)-N-(4-methoxyphenyl)azetidin-2-one (28b)
4.13. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-diethylamino-N-(4-methoxyphenyl)azetidin-2-one (28c)
4.14. (±)-(3S,4S)-3-(2-Chlorophenyl)-3-diisobutylamino-N-(4-methoxyphenyl)azetidin-2-one (28d)
4.15. Synthesis of (±)-(3R,4S)-3-Allyloxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)azetidin-2-one (31a)
4.16. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-N-(4-methoxyphenyl)azetidin-2-one (31c)
4.17. Synthesis of 3-acetoxy-N-(4-methoxyphenyl)-4-phenylazetidin-2-one (31e)
4.18. Synthesis of (±)-(3R,4S)-N-(4-methoxyphenyl)-3-methylsulfonyl-4-phenylazetidin-2-one (35a)
4.19. (±)-(3R,4S)-3-Benzenesulfonyl-N-(4-methoxyphenyl)-4-phenylazetidin-2-one (35b)
4.20. (±)-(3R,4S)-N-(4-Methoxyphenyl)-4-phenyl-3-(4-toluenesulfonyl)azetidin-2-one (35c)
4.21. Synthesis of (±)-(3R,4S)-4-(2-chlorophenyl)-3-hydroxy-N-(4-methoxyphenyl)-3-methylazetidin-2-one (38d)
4.22. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-hydroxy-N-(4-methoxyphenyl)-3-(2-propenyl)azetidin-2-one (38e)
4.23. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-hydroxy-N-(4-methoxyphenyl)-3-phenylazetidin-2-one (38g)
4.24. Synthesis of (±)-(3R,4S)-3-allyloxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)-3-methylazetidin-2-one (39a)
4.25. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-N-(4-methoxyphenyl)-3-methylazetidin-2-one (39c)
4.26. Synthesis of (±)-(3R,4S)-3-acetoxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)-3-methylazetidin-2-one (40d)
4.27. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)-3-(2-propenyl)azetidin-2-one (40e)
4.28. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-N-(4-methoxyphenyl)-3-phenylazetidin-2-one (40g)
4.29. Synthesis of (±)-(3S,4S)-3-ahloro-4-(2-chlorophenyl)-azetidin-2-one (25a)
4.30. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-iodoazetidin-2-one (25b)
4.31. (±)-(3S,4S)-3-Azido-4-(2-chlorophenyl)azetidin-2-one (25c)
4.32. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-propylaminoazetidin-2-one (29a)
4.33. (±)-(3S,4S)-3-Benzylamino-4-(2-chlorophenyl)azetidin-2-one (29b)
4.34. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-diethylaminoazetidin-2-one (29c)
4.35. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-diisobutylamino-azetidin-2-one (29d)
4.36. (±)-(3R,4S)-3-Allyloxy-4-(2-chlorophenyl)-azetidin-2-one (32a)
4.37. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-propoxyazetidin-2-one (32b)
4.38. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-azetidin-2-one (32c)
4.39. (±)-(3R,4S)-3-Methylsulfonyl-4-phenylazetidin-2-one (36a)
4.40. (±)-(3R,4S)-3-Benzenesulfonyl-4-phenylazetidin-2-one (36b)
4.41. (±)-(3R,4S)-4-Phenyl-3-(4-toluenesulfonyl)azetidin-2-one (36c)
4.42. (±)-(3R,4S)-3-Allyloxy-4-(2-chlorophenyl)-3-methylazetidin-2-one (41a)
4.43. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methyl-3-propyloxyazetidin-2-one (41b)
4.44. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-3-methylazetidin-2-one (41c)
4.45. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-3-methyl-azetidin-2-one (41d)
4.46. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-3-(2-propen-yl)azetidin-2-one (41e)
4.47. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-3-propylazetidin-2-one (41f)
4.48. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-3-phenylazetidin-2-one (41g)
4.49. Synthesis of (±)-(3S,4S)-3-chloro-4-(2-chlorophenyl)-N-methylthioazetidin-2-one (19a)
4.50. (±)-(3S,4S)-4-(2-Chlorophenyl)-3-iodo-N-methylthioazetidin-2-one (19b)
4.51. (±)-(3S,4S)-3-Azido-3-(2-chlorophenyl)-N-methylthioazetidin-2-one (19c).
4.52. (±)-(3S,4S)-N-Methylthio-3-propylaminoazetidin-2-one (26a)
4.53. (±)-(3S,4S)-3-Benzylamino-N-methylthioazetidin-2-one (26b)
4.54. (±)-(3S,4S)-3-Diethylamino-N-methylthioazetidin-2-one (26c)
4.55. (±)-(3S,4S)-3-Diisobutylamino-N-methylthioazetidin-2-one (26d)
4.56. (±)-(3R,4S)-3-Allyloxy-4-(2-chlorophenyl)-N-methylthioazetidin-2-one (30a)
4.57. (±)-(3R,4S)-4-(2-Chlorophenyl)-N-methylthio-3-propoxyazetidin-2-one (30b)
4.58. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-N-methylthioazetidin-2-one (30c)
4.59. (±)-(3R,4S)-3-Methylsulfonyl-N-methylthio-4-phenylazetidin-2-one (33a).
4.60. (±)-(3R,4S)-3-Benzenesulfonyl-N-methylthio-4-phenylazetidin-2-one (33b)
4.61. (±)-(3R,4S)-N-(Methylthio)-4-phenyl-3-(4-toluene-sulfonyl)azetidin-2-one (33c)
4.62. (±)-(3R,4S)-3-Allyloxy-4-(2-chlorophenyl)-3-methyl-N-methylthioazetidin-2-one (37a)
4.63. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methyl-N-methylthio-3-propoxyazetidin-2-one (37b)
4.64. (±)-(3R,4S)-4-(2-Chlorophenyl)-3-methoxymethoxy-3-methyl-N-methylthioazetidin-2-one (37c)
4.65. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-3-methyl-N-methylthioazetidin-2-one (37d)
4.66. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-N-methylthio-3-(2-propenyl)azetidin-2-one (37e)
4.67. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-N-methylthio-3-propylazetidin-2-one (37f)
4.68. (±)-(3R,4S)-3-Acetoxy-4-(2-chlorophenyl)-N-methylthio-3-phenylazetidin-2-one (37g)
4.69. (±)-(3R,4S)-4-(3-Chlorophenyl)-3-methoxyazetidin-2-one (43a)
4.70. (±)-(3R,4S)-4-(4-Chlorophenyl)-3-methoxy-N-methylthioazetidin-2-one (43b)
4.71. (±)-(3R,4S)-4-(2-Iodophenyl)-3-methoxy-N-methylthioazetidin-2-one (43f)
4.72. (±)-(3R,4S)-4-(3-Iodophenyl)-3-methoxy-N-methylthioazetidin-2-one (43g)
4.73. (±)-(3R,4S)-4-(4-Iodophenyl)-3-methoxy-N-methylthioazetidin-2-one (43h)
4.74. (±)-(3R,4S)-4-(2,4-Dichlorophenyl)-3-methoxy-N-methylthioazetidin-2-one (43i)
4.75. (±)-(3R,4S)-4-(2,6-Dichlorophenyl)-3-methoxy-N-methylthioazetidin-2-one (43j)
4.76. (±)-(3R,4S)-3-Methoxy-4-(2-methoxyphenyl)azetidin-2-one (43l)
4.77. (±)-(3R,4S)-3-Methoxy-N-methylthio-4-(2-nitrophenyl)-azetidin-2-one (43n)
4.78. (±)-(3R,4S)-3-Methoxy-N-methylthio-4-(4-propenyl-oxyphenyl)azetidin-2-one (43q)
4.79. (±)-(3R,4S)-4-(4-Hydroxyphenyl)-3-methoxy-N-methylthioazetidin-2-one (43r)
4.80. (±)-(3R,4S)-4-Biphenyl-3-methoxy-N-methylthioazetidin-2-one (43s)
4.81. (±)-(3R,4S)-4-Fluorenyl-3-methoxy-N-methylthioazetidin-2-one (43t)
4.82. Testing of antimicrobial susceptibilities (Kirby–Bauer well diffusion)
4.83. Culture preparation
4.84. Antimicrobiological testing
4.85. Determination of minimum inhibitory concentrations
Acknowledgements
References