WO 2013/086415 Al 13 June 2013 (13.06.2013) W P O P C T
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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/086415 Al 13 June 2013 (13.06.2013) W P O P C T (51) International Patent Classification: Irosha [LK/US]; 2007 Huron Parkway #2, Ann Arbor, C07D 265/34 (2006.01) Michigan 48104 (US). KIRCHHOFF, Paul D. [US/US]; 9670 Sherwood Drive., Saline, MI 48176 (US). (21) International Application Number: PCT/US2012/068570 (74) Agent: CASIMIR, David A.; Casimir Jones, S.C., 2275 Deming Way, Suite 310, Middleton, WI 53562 (US). (22) International Filing Date: 7 December 2012 (07.12.2012) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 61/569,100 9 December 201 1 (09. 12.201 1) US KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (71) Applicant: THE REGENTS OF THE UNIVERSITY ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, OF MICHIGAN [US/US]; 1600 Huron Parkway, 2nd NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, Floor, Ann Arbor, Michigan 48109-2590 (US). RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (72) Inventors; and ZM, ZW. (71) Applicants : SHOWALTER, Hollis D. [US/US]; 3578 Lamplighter Dr., Ann Arbor, Michigan 48103 (US). GAR¬ (84) Designated States (unless otherwise indicated, for every CIA, George A. [US/US]; 700 Madison Place, Ann Arbor, kind of regional protection available): ARIPO (BW, GH, Michigan 48103 (US). XU, Hao [CN/US]; 2001 Medford GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Road #F240, Ann Arbor, Michigan 48104 (US). ATWAL, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Sumandeep K. [US/US]; 2762 Sagebrush Circle #104, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Ann Arbor, Michigan 48103 (US). NAWARATHNE, [Continued on nextpage] (54) Title: ANTIMICROBIAL COMPOUNDS (57) Abstract: Provided herein is technology relating to antimicrobial com pounds and particularly, but not exclusively, to analogs of rifalazil having in creased inhibition of RNA polymerase and decreased induction of human cy tochrome P450. The compounds have an increased affinity for a bacterial RNA polymerase (e.g., a MTB RNA polymerase) and a decreased affinity for a human pregnane X receptor. Thus, in some embodiments, the steric clash Y of A or R with residues in the binding pocket of the human pregnane X re . J . ceptor reduces an affinity of the compound for the human pregnane X recept or. Consequently, in some embodiments the steric clash thus reduces the in duction (e.g., an activity) of a cytochrome P450 and/or other related proteins. 1 w o 2013/086415 A i II 11 II I Illlll III III III III II I III II I II MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Published: SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, — with international search report (Art. 21(3)) GW, ML, MR, NE, SN, TD, TG). ANTIMICROBIAL COMPOUNDS FIELD OF INVENTION Provided herein is technology relating to antimicrobial compounds and particularly, but not exclusively, to analogs of rifalazil having an increased inhibition of RNA polymerase and a decreased induction of human cytochrome P450. BACKGROUND Tuberculosis (TB) is a contagious and deadly disease that has reached pandemic proportions. According to the World Health Organization (WHO), 8 to 10 million new cases of TB are diagnosed each year and 2 to 3 million people die from the disease each year. Consequently, the causative agent of TB, Mycobacterium tuberculosis, is a leading cause of adult deaths from infectious disease. A high proportion of these newly diagnosed cases and deaths occurs in HIV-positive people, and a significant number of AIDS deaths in Africa is attributable to TB infections. Global population growth is increasing the disease burden and, in turn, posing a continuing health and financial burden in various parts of the world, particularly in Asia and Africa. TB is caused predominantly by Mycobacterium tuberculosis (MTB), an obligate aerobic bacillus that divides at an extremely slow rate. The chemical composition of its cell wall includes peptidoglycans and complex lipids, in particular mycolic acids, which are a significant determinant of its virulence. The unique structure of the cell wall of MTB allows it to lie dormant for many years as a latent infection, particularly as it can grow readily inside macrophages, hiding it from the host's immune system. While TB has grown to be a pandemic, no new TB drugs have been introduced into clinical use in the last four decades. Furthermore, the continuing rise in multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) has contributed to the dire need for new TB antibiotics. Drugs that are active against resistant forms of TB are less potent, more toxic, and need to be taken for an extended period of time (e.g., continuously for more than 18 months). Also, the recent emergence of virtually untreatable extensively drug-resistant TB (XDR-TB) poses a new threat to TB control worldwide. One particularly difficult problem is that the effective treatment of TB in persons co-infected with HIV is complicated by drug-drug interactions. The rifamycins are the most commonly used drugs for TB, and semisynthetic derivatives have been reported that show improved antimycobacterial activities. These include rifampin (RMP, see Figure l), which is the cornerstone of current short-term TB treatment. Amongst newer derivatives, rifalazil (RLZ, see Figure l ) has proved most interesting because of its potency and relative lack of toxicity in early rodent studies. RLZ is an exceedingly potent rifamycin derivative that is 16 - 256 times more potent than RMP and is particularly effective against many of the RMP-resistant strains of MTB. Several early studies involving MTB strains with various rpoB mutations clearly indicated that the mutations identified with RMP- resistant, rifapentine-resistant, and rifabutin-resistant strains retained sensitivity to RLZ. RLZ and its benzoxazinorifamycin analogs also have showed excellent activity against other organisms with RMP-resistant mutations, including Streptococcus pyogenes, Chlamydia trachomatis, and Chlamydia pneumonia. In mouse in vivo efficacy studies, RLZ has been shown to be more potent than RMP, including having activity against some RMP-resistant strains. Longer term MTB studies in combination with other agents indicated the same level of cure could be achieved with a shorter duration of treatment (e.g., at least one-half of the time) with RLZ as compared to RMP. In PK studies, RLZ has shown a high volume of distribution and produced tissue levels in rats up to 200 times those in plasma. It displayed a very long half-life (60-100 hours) in human trials. One drawback to using the rifamycins in TB treatments is their many drug- drug interactions. This effect appears to be minimized with RLZ as shown in rat and dog studies. These studies also showed RLZ not to be an inducer of hepatic cytochrome P450 (Cyp450). Unfortunately, in a series of phase I and phase II clinical trials, RLZ proved to be quite toxic, with most adverse effects associated with a flu-like syndrome and leucopenia even at lower dose levels. Hence, its development for TB indications has been suspended. SUMMARY Provided herein is technology relating to antimicrobial (e.g., anti- mycobacterial, anti-TB) compounds and particularly, but not exclusively, to analogs of rifalazil having increased inhibition of RNA polymerase (e.g., through an interaction with a sigma factor or, e.g., through an interaction with another subunit of the RNA polymerase). In addition, the compounds also demonstrate decreased induction of human cytochrome P450. Accordingly, embodiments of the technology provide compounds having the formula wherein R is an independent chemical moiety that increases an inhibiting interaction of the compound with an RNA polymerase relative to rifalazil and causes a steric clash of the compound with a side chain in a binding pocket of a human pregnane X receptor and wherein A is H — or is an independent chemical moiety that increases an inhibiting interaction of the compound with an RNA polymerase relative to rifalazil and causes a steric clash of the compound with a side chain in a binding pocket of a human pregnane X receptor. In some embodiments, A is H- and R is Et2NCH2CH2-, in some embodiments A is H- and R is in some embodiments, A is H- and R is and in some embodiments A is and R is In some embodiments, A is selected from the group consisting of H- and . In some embodiments R comprises herein R' is selected from the roup consisting of H, methyl, eth l, i-Pr, and i-Bu? R" comprises , and/or and n = 1-3. The compounds have an increased affinity for a bacterial RNA polymerase (e.g., a MTB RNA polymerase) and a decreased affinity for a human pregnane X receptor. Thus, in some embodiments, the steric clash of A or R with residues in the binding pocket of the human pregnane X receptor reduces an affinity of the compound for the human pregnane X receptor.