Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (II)

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed. Marinopyrrole A was reported to show antibiotic activity against MRSA in 2008. After we reported the first total synthesis of (±)-marinopyrrole A, we designed and synthesized a series of marinopyrrole derivatives. Our structure activity relationship (SAR) studies of these novel derivatives against a panel of Gram-positive pathogens in antibacterial assays have revealed that a para-trifluoromethyl analog (33) of marinopyrrole A is ≥63-, 8-, and 4-fold more potent than vancomycin against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA, respectively. The results provide valuable information in the search for new-generation antibiotics.

Acylation of Pyrroles and their Free (N‐H)‐Derivatives via Palladium‐Catalyzed Carbopalladation of Nitriles

“…Gratifyingly, decreasing the catalyst loading to 5 mol% of Pd(OAc) 2 did not affect the yield. Replacing Pd(OAc) 2 with other palladium sources such as PdCl 2 , Pd 2 (dba) 3 and Pd(acac) 2 decreased the yield (entries [12][13][14]. Further screening of the reaction with respect to ligands revealed that phosphine ligands did not work under comparable conditions (entries 15-17).…”

“…[1] For instance, Tolmetin I, Zomepirac II and Ketorolac III as non-steroidal anti-inflammatory drugs (NSAID) have been shown to reduce hormones that cause pain and swelling, have antipyretic actions and are used as analgesics, respectively ( Figure 1). [2] Moreover, marinopyrrole derivatives IV are identified to display significant antibacterial activity against methicillin-resistant Staphylococcus aureus [3] and cytotoxicity against HCT-116 human colon cancer cells. [4] 2-Acylpyrroles are also versatile intermediates for the synthesis of alkaloids and other related heterocycles.…”

Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors

“…Starting from our previously reported compound 2 [35], mono-ketone 4 was obtained in 73% yield over two steps by introduction of ortho- methoxy- para- methylphenyl group ( 3 was not isolated) followed by IBX oxidation (Scheme 1). Removal of TBDMS protecting group with TBAF gave alcohol 5 in 90% yield.…”

“…Bisketone 8 was obtained in 54% yield after introduction of second ortho- methoxy- para- methylphenyl group (without isolation of 7 ) followed by IBX oxidation. Removal of para- toluenesulfonyl group with KOH generated 9 in 98% yield, which was converted to 10 in 65% yield by chlorination with NCS [35]. The final symmetrical marinopyrrole derivative 24 was obtained in 85% yield after demethylation using BBr 3 /DCM [36].…”

“…The final symmetrical marinopyrrole derivative 24 was obtained in 85% yield after demethylation using BBr 3 /DCM [36]. Using our previously reported intermediate 11 [35] as a starting material, palladium-mediated substitution of the triflate 11 with ethynyltrimethylsilane furnished 12 in 74% yield (Scheme 2). Demethylation of 12 using BBr 3 /DCM gave 13 in 53% yield, which was converted to the final symmetrical marinopyrrole 1–3 in 78% yield.…”