Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues

Abstract

SummaryAurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress

“…Based on these findings we tested if small-molecule inhibitors can block the activity of cytochrome bd in M. smegmatis . The aurachin class of quinone analogs has been reported as inhibitors of a variety of quinone-modifying enzyme 40 41 42 . Within this class, aurachin D was previously shown to preferentially inhibit E. coli cytochrome bd as compared with other quinone-modifying enzymes 42 .…”

4‐Quinolone Derivatives and Their Activities Against Gram‐negative Pathogens

“…Although some 4-quinolones with C-3 acetic acid [90], amide [91][92][93][94][95], aminothiazol [96,97], azetidinones [98], hydrazones [99-102], 1,2,4-triazole [103], dihydrotestosterone [104], hydroxamic acid [105], indole [106], thiazolidinone [107], and C-3 amide linked LVFX dimers [108] as well as C-3 decarboxylated 4-quinolones [109][110][111] displayed considerable potency against Gramnegative organisms, most of them only exhibited weak to moderate activities, reflecting modification of the carboxylic acid at C-3 position resulted in loss of the activity generally. Manipulation of the substituent at C-5 position of 4-quinolones has some influence on the antibacterial potency against Grampositive bacteria, and -H is the most common group at this position.…”

Synthesis of aurachins B and H

“…7,8) These intriguing biological profiles as well as the unique molecular architectures featuring a 4-quinolone or quinoline N-oxide nucleus prompted synthetic efforts toward this family of natural products, which culminated in the total synthesis of aurachin D (4) through the Conrad-Limpach cyclization by two research groups. 9,10) We also succeeded in the total synthesis of aurachins C (3), D (4), and L (5) by utilizing reductive cyclization of δ-nitro ketone intermediates with zinc or iron as the key step. 11) All of the previous synthetic studies on aurachins have thus been directed toward those with an oxygen-functionality at C4 and a farnesyl chain at C3 (see 3-5) or their analogs.…”

“…11) All of the previous synthetic studies on aurachins have thus been directed toward those with an oxygen-functionality at C4 and a farnesyl chain at C3 (see 3-5) or their analogs. [8][9][10][11][12][13] However, synthesis of aurachin B (2) or its analogs with another substitution pattern, namely, an oxygen functionality at C3 and a farnesyl chain at C4, has never been reported so far, which probably means the difficulty to realize the aurachin B-type substitution pattern. As for the synthesis of aurachins A (1) and H (6), the absolute configurations of which are still unknown, or their analogs that are characterized by the presence of a dihydrofuran ring unit, only one report on the synthesis of analogs of aurachin H has been disclosed by Müller and Nay's group.…”

“…As for the synthesis of aurachins A (1) and H (6), the absolute configurations of which are still unknown, or their analogs that are characterized by the presence of a dihydrofuran ring unit, only one report on the synthesis of analogs of aurachin H has been disclosed by Müller and Nay's group. 9) In their synthesis, however, treatment of quinoline intermediates possessing a geranyl or farnesyl side chain with m-chloroperbenzoic acid to oxidize the quinoline nitrogen as well as to epoxidize the Δ 2' double bond on the side chains was accompanied by unfavorable overepoxidation of a distal double bond, 9) which means that the oxidative approach to the quinoline N-oxide nucleus is not suitable not only for the synthesis of 6 but also for that of 1 and 2. As part of our ongoing efforts toward the total synthesis of aurachins, 11) we describe herein the first total synthesis of aurachin B (2) and (2'S,3'R)-aurachin H (6) exploiting our reductive approach to the quinoline N-oxide structural motif.…”