The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs

Abstract

Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 μg/mL, representing a significant improvement in antitubercular potency in this class of compounds.

MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis

“…To build on its inherent safety and efficacy, but improve upon its potency and pharmacokinetics, we examined a series of compounds structurally-related to FSM 31 , 32 . These compounds differ structurally from FSM in the degree of unsaturation, terminal acetamide and/or presence of a lipophilic diester.…”

Potent, specific MEPicides for treatment of zoonotic staphylococci

“…Due to their charged nature, phosphonic acid antibiotics have poor cellular penetration and bioavailability, and serum half-lives are relatively brief(23,25,40). In the ongoing effort to develop new treatments for malaria and tuberculosis by improving upon the drug-like properties of phosphonates, numerous lipophilic ester prodrugs that target DXR have been generated(41–53) Our phosphonate parent compounds (1 and 3) are similar in anti-staphylococcal potency to FSM and FR-900098 (Table 1); however, lipophilic modification of either compound dramatically improves potency (in most cases by 100-fold) against both S. schleiferi and S. pseudintermedius (compare compound 1 to its prodrug, compound 2, and compound 3 to its prodrug, compound 4) (Table 1). As expected, prodrugs 2 and 4 poorly inhibit purified recombinant S. schleiferi DXR in vitro , since cleavage of the prodrug moiety is required for activity (Table 1).…”

Structure–Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis

“…(6, 36) Compound 5 was hydrolyzed under acidic conditions (36) and then acylated (10) with a series of acid chlorides to give N -acyl analogs 6a–n . Removal of the benzyl group using either hydrogenolysis or BCl 3 (10, 37) yielded diethyl esters 7a–n . Treatment of these esters with trimethylsilylbromide (38) and BSTFA, (10, 39) followed by sodium hydroxide gave monosodium salts 8a–n .…”

“…(6–10) TB is still responsible for nearly 2 million deaths each year and threatens public health in both developed and developing countries. (11–13) Gram-negative Yersinia pestis , a bacterial cousin of Mtb, continues to infect individuals worldwide.…”