Syntheses of the First Selenium‐Containing Bicyclic β ‐Lactams as Potent Antimicrobial Agents

Abstract

Syntheses of the cis-configurated isodethiaselenapenam 5 (Scheme 1 ) as well as the isodethiaselenacephems 29 and 31 (Scheme 2) were accomplished, in which the key step involved addition of Se to the corresponding carbanions of 1,25, and 27 followed by internal alkylation.8-Lactams 29 and 31 were found to possess biological activity against several pathogenic microorganisms in v i m . The electronic activation of the Iactam moiety in the isodethiaselenacephem 31 and the corresponding isocephem 33 remarkably enhanced their biological activity. Isodethiaselenacephem 31 was more toxic than isocephem 33 in experimental animals.Introduction. -Elemental sulfur reacts with phosphoryl carbanions to give phosphorylmethane thiols, which upon treatment with alkylating agents lead to phosphorylmethyl sulfides [l] [2]. In this connection, we found that the reaction of phosphoryl carbanions of monocyclicp-lactams (i.e. 1) with elemental sulfur gave the corresponding sulfido salts. These salts underwent an internal SN2 of the mesylate functionality to afford the corresponding bicyclic / l -1actams (e.g. 2) [3]. Herein, we report our findings on the exploration of the reaction of the phosphoryl carbanion of 1 and sulfonyl carbanions of 25 and 27 with elemental selenium. These reactions afford the corresponding isodethiaselenapenam 5 (Scheme 1) and isodethiaselenacephems 29 and 31 (Scheme 2). In addition, we report a new synthesis of biologically active isocephem 33 [4] (Scheme 2) by reaction of the sulfonyl carbanion of 27 with elemental sulfur.

Synthesis and characterization of novel trans-3-benzyl/(diphenyl)methyl/naphthyl seleno substituted monocyclic β-lactams: X-ray structure of trans-1-(4′-methoxyphenyl)-3-(diphenyl)methylseleno-4-(4′-methoxyphenyl)azetidin-2-one

“…The bond angle of C(14)eSe(1)eC(1) bond in (6b) is 97.07 (16) indicating the distortion of sp 3 carbon from its regular tetrahedral geometry and established the 'V' shaped geometry about CeSeeC bond. Further, the trans stereochemistry between C3eH and C4eH of the b-lactam 5e7 was evident through torsional angle between Se(1)eC (14)eC (16) 19)] of other crystal unit respectively (Fig. 1, Table 4).…”

“…The SeeC bond length between Se and C-3 of b-lactam 6b [SeeC (14), 1.94 A] lie within the range (1.90e1.95 A), reported for several organoseleno compounds possessing SeeC bond [38,39]. However, the SeeC bond length between Se and methine carbon atom of (diphenyl)methyl is slightly longer i.e., [SeeC(1), 1.99 A], indicating the weakening of CeSe bond as a result of another phenyl substitutient.…”

“…Pioneering research contributions in synthesis of bicyclic seleno-b-lactams such as selenapenems and selenacephames have been made by Perrone et al [11], Thomas et al [12], Fujita et al [13], Hakimelahi et al [14] and Gallagher et al [15,16]. In addition, Ohshiro et al [17], Liebscher et al [18], Torchiarolo et al [19] and Turos et al [20] have developed different strategies for the synthesis of monocyclic seleno-b-lactams.…”

Microwave Assisted Stereoselective Synthesis and Antibacterial Activity of New Fluoroquinolinyl-β-lactam Derivatives

“…Apart from their potent antibacterial activity [1] they are also known to possess antifungal [2], antiparkinsonian [3] and antitumor [4] activities. Thus they are agents of choice for microbial infectious diseases in the current therapeutic index [5]. Tremendous efforts have been made for the synthesis and structural modi®cation of thelactam nucleus to increase antimicrobial activity and pharmacokinetic performance [6].…”

Synthesis and reactions of some new selenolo[2,3-c]pyridazines

“…There are data showing that organoselenium compounds are capable of sensitizing processes in the living organism, and there are four known naturally occurring proteins containing the selenium atom. Therefore, despite the high toxicity of selenium compounds [7-9], many of them have been prepared as and anticancer agents [10-15] and for other medicinal effects like antiviral [16][17][18], antimicrobial [19][20][21][22], and fungicidal [23][24][25] activities. Heterocyclic annelated pyridazines also attract considerable attention, which arises mainly from the large variety of interesting pharmacological, herbicidal, insecticidal, and fungicidal activities [26][27][28][29][30].…”