Medicinal Significance of Nitroimidazoles - Some Recent Advances

Journ al of Scientitic & In dustri al Research Vo l. 62 , Jul y 2003 , pp 659-665

V K Kapoor' , Renu Chadha, Praveen K Venisetty and S Prasanth

. Uni vers it y In stitute of Pharmaceuti cal Sciences, Panj ab University, Chandi garh 160014

Received: 29 February 2002; revised: 12 Ap ril 2002; accepted: II September 2003

Nitroimidazoles have th erapeutic uses as anaerobic anti bacteri als and ant i protozoal agents. Recently, th ey ha ve been founcito possess other int eres tin g biological ac ti vit ies of therapeutic potenti al such as, radiosensi ti zers in treatment of cancer, co ntrol of fertili ty , and antitubercul ar therapy. Variolls aspects on th e chemistry and modes of ac ti on of nitroill1id azoles are di scussed. Key words: Nit ro imi ciazoles, Therapeutic uses of nitroill1idazoles, Biol ogical acti vities

status not onl y as antimicrobials but havin g other Introduction interesting biological profil es, discovered recentl y. Medicin al chemists have often been skeptical about the use of nitro group in potential medicinal agents because certain untowards observati ons have been made with regard to the nitrocompounds. Compounds like trinitrotolu ene, employed in expl os ives arsenals, cause methemoglobinaemia Azyomycin (1) Metronidazole (2) following skin absorption, and picric acid useful as antiseptic, turns out to be a systemi c poison. Classification of Nitroimidazoles Chl oramphen icol, an antibacterial di scovered in 1948, was found to have a nitrophenyl sysytem. Since then, Depending on the positions avail able 111 other nitroheterocycles have been di scovered among imidazole heterocycle, nitroimidazoles have been antimicrobi al agents and have been used in severe classified as 2-nitro, 4-nitro-, and 5-nitroimidazoles. typhoid and other salmone ll al infections. The Out of them, 5-nitroimidazoles have established di scovery of azomycin (1), a 2-nitroimidazole, by themselves as significant therapeutic agents with i Nakamura and demonstration of its antibacterial anti protozoal and antibacterial properites. 2 antitrichomonal properti es , revolutionised the area of nitroimidazoles. Azomycin became the chemical lead 2-Nitroimidazoles fo r extensive syntheti c development of over hundered compounds. This resulted in the emergence of a Azomycin (1) di scovered from the extract of soil compound now known as metronidazole (2), which Streptomyces cultures was the first 2-nitroimidazole was introduced as a che motherapeutic agent in 1960 to exhibit activity against several protozoans, in Europe and in 1963 in the US. It became a drug of specifically trichomonads. It provided a prototype for choice in the treatment of several protozoal infecti ons the development of other nitroimidazoles, such as and infecti ons caused by obligate anaerobes. The misonidazole (3), which showed activity again st present communication reviews the development of intestinal amoebiasis in rats similar to that of nitroimidazoles as medicinal agents with their current metronidazole3.4. Misonidazole also find therapeutic use in the treatment of neoplasti c diseases5 * Author for correspondencc Benznidazole (4) is useful in the treatment of South e·· mail: ren ukchadha@rediITmail .co ll1 American trypanosomiasis (Chagas' di sease) due to 660 J SCI IND RES VOL 62 JULY 2003

infecti on with Trypanosoma cru zi, especially in early development of other clinically useful antibacterial acute stage of the di sease. and antiprotozoal drugs, like ti niclazole (6), panidazole (7), ornidazole (8), secnidazole (9), carnidazole (10), and ternidazole (11)5.

fH2C H2 < ~N O,N,(,(CH,

Mi sonidazole (3) Benzindazole (4 ) Tinidazole (6) Panidazole (7) 4-Nil m imidazole.\" As such, th ere appears to be no report on th e anti protozoal or antibacterial effects of OH OH 4-nitroimidazole derivatives. However, a drug I I CH CHCH CI CH CHCH azathioprine (5) which has 4-nitroimidazole-5-·yl 2 2 2 3 moeit y attached to purine through sulphur has I I show n promise as an immunosuppressant. O,N'(r CH, O,N'(r CH, CH I .3 N"-... s ----<, II Ornidazole (8) Secnidazole (9) )C\ N N °2 s N II CH2CH2CH20H CH CH NHCOCH ~ 2 2 3 I N I H O,N'('(CH, Azathioprine (5) O,N--(,(CH,

5 -NiI milllidm.nies Carnidazole (10) Ternidazole (11) S-Nitroimidazoles constitute th e l,irgest group of nitroimidazoles with anti protozoal and antibacterial actIvItIes. M etronidazole, 1-(2-hydroxyethyl)-2- Nimorozole (12) which lacks methyl at postion methyl-S-nitroimidazole (2) is one of the most 2, and other 5-nitroimidazoles havin g varied extensively used drug in the treatment of substituents at position 2 are: dime trid azole (13), tri chomoniasis, amoebiasis, ;JI1d giardi asis and shown ipronidazole (14), ronidazole OS), 'MP' to be active against anaerobic bacteria. It is the most nitroimidazole (16), 'MCA' nitroimidazole (17), and active agent available against obli gate anaerobes and azanidazole (18). Ronidazole is used in veterinary is of major value in the treatment of seri ous infections practice also for the treatment and control of swine 3 due to these organisms . Metronidazole has been a dysentry. subject of extensive chemi cal modifications to improve its bi oavail abilit/ . r-\ CH CH -N 0 Foll owing the sll ccess with metronidazole, a 12 2 ~ hectic acti vit y of synthesising and testing other 5- nitroimidazole was initiated. As the 1-(2- o,N-<'-fj hydroxyeth yl) side chain at posi tion I of metron id azole is readil y ox idi sed metabolically, repl aceme nt of this side c hain resulted in th e Nimorazole (12) Dimetridazole (13) KAPOOR el al.: MEDICINAL SIGNIFICANCE OF NITROIMIDAZOLES 66 1

CH Mechanism of Antimicrobial Actions of 3 CH I /. 3 5-Nitroimidazoles N 02 \CN-Y-CH The mechani sm of acti on of nitroimidazoles has ~ II " CH R N 3 been studied in detaiI . " • T he nitroimidazoles are selectively toxic to anaerobic or microaerophilic Ipronidazole (14) Ronidazole (15) mi croorganisms and for anoxic or hypoxic cell s. The S-nitroimjdazoles, as represented by metronidazole, require metabolic activation by sensiti ve organi sms for their antimicrobial effect. After the drug enters into the cell the nitro group of the imidazole heterocycle accepts electrons from the electron transport protein s with sufficie ntl y low negati ve redox 'MF' Nitroimid azole (16) 'MeA' Nitroimida7.0 le (17) potential such as, flavoproti ens in cluding xanthine oxidase, NADPH cyt P450 reductase and NADPH cyt c reductase in mammalian cell s and ferredoxin or th eir equivalent, such as pyru vate dehydrogenase ferredoxin oxidoreductase in protozoan or bacte ri a. The rate of intracellular reducti on is important because it determines the rate of drug uptake into the cell via a concentration gradient. The complex Azanidazole (18) reduction is catalysed by nitroreductase in mammalian cell and by iron-sulphur complexes in other case. The electrons are supplied by e ither A new 5-nitroimidazole fexinidazole (HOE 239) reduced nicotinamide adenine dinucleotide phospahtt' (19) with a 4-methylthio- phenoxymethyl group at (NADPH) or sulphide. The reduction of postion 2 was found to be hi ghl y acti ve against cure nitroimidazoles is a complex process in volvin g ex perimental murine eNS-trypanosomiasis with sequential addition of an electron, protonation and a I d treatment, when given in combination with 6 disprotonati on, as shown in F igure I. The che mi call y melarsoprol . Sulphimidazo\e (20) is th e most reactive intermediates, formed during the electron recent compound in wh ich a p-aminobenzene reduction of the nitro group to the corresponding sulph onamide' moeity has been attached at hyd roxylamine, account for the antimicrobial activity position 2 of the 5-nitroimidazole rin£. It possesses a useful spectrum of ac tivity. e . -R-N02 ---( 1)

---(2) R-NO; + f-+ - R-N02H ---(3) 2R-N02H - R-N02 + R-N(OH)2 R-N(OH)2 --__ R-NO + Hp ---(4)

- - e . ---(.5) R-NO? - R-N02

Fexinidazole (19) + . ---(6) R-N02 + H - R-N OH

R-NOH + R-NO?H - R-NHOH + R-N0 ---(7) CH 2 3 e . I 0 R-NHOH - R-N HOH ---(8) ON N II._~ ---(9) 2 'i IrNHS~NH2 R-NHOH + 2H - R-NH2 + H20 \-N R", Imidazole heterocycle

Sulphimidazole (20) Figure i-Biorecl uction of nilruimiclazo\es 662 J SC I INO RES VOL 62 JULY 2003 of nitroimidazoles. The exact process by whi ch these Nitroimidazoles as Radiosensitizers in the intermedi ates destroy the cell s has not been elucidated Treatment of Cancer but it has been suggested th at these · intermedi ates The hypox ic cell s present in most of the solid react with cellul ar mac romolecul es, such as tumours, limit the successful local control of these deoxyribonu cleic ac id (DNA), protein s, and tumours by radi oth erapy of growth , essenti all y membranes. The entiti es whi ch are cytotox ic and outstripping the tumour's vascul ar sys tem, hence cause DNA damage are nitro- free radi cal and the reducing the suppl y of essenti al nutrients, parti cul arl y superox ide ani on, fo rmed by its reacti on with oxygen, oxygen. However, ti ssue oxygen tension decreases as we ll as th e products of further reducti on of nitro with di stance fro m th e capillary and gradu all y fall s to group [i.e. nitroso (R-NO), nitroso-free radi cal a level in sufficient for cell di vision. Eventuall y th e (R-NO)] or hydroxylam in e (R-NHOH). oxygen deprived cell s die and thi s causes th e local Pharmacokinetics necros is observed in mos t solid tu mours. A viab le hypoxi c cell , whi ch occurs in the in terface regions The ph armacok in eti cs of nitroimidazo les, between the we ll-oxygenated ti ssue and th e necrot ic in clu din g th at of metronidazole, has been studied regions, are radi ati on resistant relati ve to ox ic ce ll s. in tensive l/ ' 2 They are readily absorbed foll owin g So the radi ati on resistance is th e largest fac tor ad min istrati on by mouth with excell ent degrees of influencin g local tumour control by radiati on. bioava il ability. Peak pl asma concentration of approx imately 5 and 10 /-lg/mL are ac hi eved usuall y In the earl y I 970s, researchers in Canada and wi thin I to 2 h of sin gle dose ad ministrati on of 250 England , di scovered that ni trofurans and i.lnd 500 mg, res pecti ve ly, of metronidazo le. nitroimidazoles are radi osensiti zers of hypox ic Nitroimi dazo les ge t widely di stributed in the body. (oxygen deficient) cell s. Cellul ar response to ioni zin g Metronid azo le is reported to appear in mos t of body radi ati on IS strongly influenced by oxygen ti ssues and flu ids , li ke bil e, bone, breast mil k, concentration; hypox ic ce ll s are mu ch mo re resistant cereberospin al flui d, seminal flui ds, and vagin al to radi ati on damage than are normal ly oxygenated secreti ons. cell s. The sensiti zin g effect of molecular oxygen is probably a consequence of th e rapid chemi cal Metro nidazole ge ts metaboli zed by th e li ver reacti ons between oxygen and short-li ved free th rough sid e chain ox idation and glu curonide radi cals generated by radi ati on absorption. It has been format ion. The principa l ox ida ti on metabolites are suggested that electro n affini c (or eas il y reduced) 1-(2-hydrox ye th y 1)-2-hydrox ymeth yl-5-n it ro i midazole chemi cal s mi ght mimi c the sensitizin g ac ti on of whi ch also have anti bacteri al activity . It is detectabl e oxygen and thereby overcome the radio res istance of in plas ma and uri ne. The other major metabolite hypox ic cell s. The di scovery of the radio sensiti zing wh ich has no anti bac teri al activity is 2-methy l-5- pro perti es of nitro-heterocycles led to th e in tense nitroil1li dazo le- I-aceti c ac id . Small amounts of interest in the medi cal applicati on of radiosensiti zers. reduced ac etami de and N-(2-h yd roxyeth yl)oxami c The correlati on between one electro n reduction acid (HOA) have also been detected in urin e. potenti al and ability of nitro compounds to act as radi osensiti ziers of hypox ic cell s i, central to the The half- li ves of 5- nitro imi dazoles va ry from 8-20 h. The va lues repo rted1 are metro nid azole (8 h), deve lopment of agents useful as adjuncts in orinidazole ( 12 - 14 h), be nznidazole (1 0.5 - 13.6 h), radi otherapy. The first e lectro n affi ni c sensitizer and secnid azo le (20 h). based on the nitro functi o nal group to be tested

Recent Advances in Othe." Biological Profiles OH

Besides hav in g anti protozoal and antibacteri al I CH CHCH 0H activity nitroimidazoles have ex hibited other 2 2 I in terestin ba bioloab ical ac ti viti es, whi ch are useful in th erapeuti cs. These are nitroimidazoles as radi o- NO sensiti zers, antifertility potenti al of nitroimidazo les, (r , and antitubercu lar profil e of certain nitri midazopyrans. Mi sonidazole Desmeth ylmisonidazole KAPOOR el al.: MEDI CINAL SIGN IFICANCE OF NITROIMIDAZOLES 663

mj sonidazole, both in vitro and in vivo. However, gastrointestinal toxicity limits the dose than can be administered clinicall y to levels that woul d be expected to provide a benefit in cancer therapy. RB 6 145 is a prod rug of RSU I 069 that has lower tox icily with similar potency.

SR - 2508 R003 - 8799 Binding of Nitroimidazoles to Hypoxic Cells - Use in Detection of Cancer clinicall y was metronidazole that was already in Nitroimidazoles are reduced under hypoxic clinical use as an anti trichomonal agent. The lead conditions to intermedi ates that bind cellul ar macromolecules. This has been exploited in the compound, however, in this seri es was 2-nitro ls imidazole, mi sonidazole, extensively in vesti gated detection of tumour hypoxia . Earl y studies ut ili zed clinicall y as radi osenti zier. The neurological toxicity 14C-labe ll ed mi sonidazole and autoradi ography, and of mi soni dazole is the major limitati on in its served to demonstrate that hypoxia does occur in applicati on !} . It has been shown that the neurotoxic pati ent 's tumours. Another approach has been to use property is due to lipophilic character. In an effort to nitroimidazole derivati ves that can be detected 6 reduce this side effect, less lipophilic 2-nitro immunohi stochemi call / . F lu orinated nitroimdazoles imidazoles, such as desmethylmisonidazole and SR- have been synthesized for use in non-in vas ive 2508 were systhesized whi ch showed less detecti on of hypoxia. neurotoxicity than mi sonidazole in keeping with their Chemosensitization lower lipophilicity. A Roche compound R003- 8799 whi ch has a basic side chain has been found to be Nitroimidazoles potentiate some chemo- superi or to mi sonidazole with improved tumour therapeutic agents, particul arl y a lk ylating agents. uptake. The improved uptake has been attributed to Hypox ia is a prerequisite fo r chemosensit ization; th e acid-base properti es of th e piperidine group in the which gives it some specificity for tumours. T hree side chain structure. During th e development of the mechani sms, whi ch have been suggested to account chemosensiti zers, numerous compounds have been for the chemosensitizati on and observed synthesized whi ch were substanti all y more efficient in experimenta ll y are depleti on of intracellular thiols: vitro than would be predicted on the basis of the modification of pharmacokinetics, and increased electron-affinity relati onship. This is particul arl y true cross-linking of DNA. of some compounds that react efficiently with Antifertility Potential of Nitroimidazoles intracelluar glutathi one". Most of these compounds show little, if any, acti vity in vivo. M ore recentl y, Ornidazole, 1-(3-c hl oro-2-hydroxy)propyl-2- derivatives of mjsonidazole which contain in a side methyl-5-nitroimidazole has been found to be an chain a monofuncti onal alkylating groups, such as effective antifertility agent in male rats onl yl 7 It acts aziridine, have been prepared. A lead compound in rapidly and reversibl y to decrease the motil ity of thi s seri es is RSU 1069, chemicall y 1-(2-nitro-l distal epididymal spermatozoa rather than on maj or 14 imidazolyl)-3-( l-aziridinyl)-2-propanoI . It has been epididymal secretions. IS It does not prevent access of found to be more efficie nt radiosensitizer than spermatozoa to eggs in the oviduct while inhibiting l9 fertilization , and reduces the acti vities of two glycolyti c enzymes of epididymal spermatozoa OH without reducing the ability of sperms to undergo 2o I capactation and acrosomal loss ill vitro. Ornidazole iH2CHCH2-N:j is used clinically for the treatment of genital tract infecti ons in both women and men and thus ha some potential as a basis for human contracepti ve agents. In ()(NO, contrast, metronidazole is reported to take 6wk to N reduce spermatogenesis and render male rats infertil e, . ? I RSU 1069 RB 6 145 as a resu I t 0 f azoospermla- . 664 1 SCIIND RES VOL 62 .I UL Y 2003

Some obsevati ons with regard to structure the S-enantiomers we re generally at least la-fold acti vity relationship fo r anti fe rtil ity potenti a l have more acti ve than the R-e nantiomers, NAP acti vity was been drawn n Of the th ree functional groups attached found to be hi ghly specifi c for the MTB complex, and to th e imidazole ring of ornidazole, viz.. methyl, nitro, showed onl y modest or no actIvIt y against and (chl orohydroxy)propyl, th e three-carbon side mycobacteria outside the MTB complex (M. avium, cha in at posilion I is essential fo r anti fe rtility acti on. M. megmatis, M.chelonae alld M. jortllitum)27 T he compounds that lack thi s side cha in , such as Over 50 NAP compounds with demonstrated 2-methyl-5 -ni iroimidazoie or those having side chains acti vity again st cultured MTB were :'creened for ill of one carbon, suc h as dimetridazole or of two vivo antitubercular activity, using a short-term murine carbons with either a hyd roxyl group, such as mode l of infecti on with an MTB reporter strain metroni dazole or chl orine, such as 1-(2-chloroeth yl )- expressing firefl y lu c iferase (rMTB-Lux). A lthough 2-llleth yl-S -nitroil1lidazole are all in acti ve. Even when PA-824 was not th e most potent N AP against cultured , the side c hain has three-carbon, suc h as ornidazole, MTB c linical isolates, it was found to be most acti ve but lacks chl oro and hydroxy functi ons, such as 1- in infected mi ce when orall y ad min istered at 25 (2,3-epox y )pro py 1-2-methyl-5-n i troi l1li dazole or mg/kg. This indicated that PA-824 mi g ht possess whi ch has a longer side c hain, such as tinidazole has more desirable pharmacokineti c properties than the no effect on fertili ty. other more potent NAP compounds that were tested. Antitubercular Profile of Certain Nitmimidazopyrans The acti vity of PA-824 against both multid ru g resistant and non-replicating mi croaerophi I ic MTB A seri es o r hi cycli c ni troimdazofurans, suggested that the NAPs act by a new mechani sm. ori gin all y in vestigated as radi osensiti zers fo r ll se in Studies on th e macromolecul ar effects of PA ·824 on cancer chemoth erap/.1, were found to possess ac ti vity MTB revealed that both protein and li pid synthesis again st cultured replicating Mycobacterium were substanti all y inhibited at drug concentrati o ns flIben:lI/osis (MTB) and had significant ill vivo and time intervals when nuc le ic ac id sy nthesis was acti vi ty in a murin e in fec ti on model"4-26 . T he lead unaffected. Lipid synthesis was not e ffected by compollnd in this seri es, CGI-· I 734 ) was mutageni c, treatment with amikacin , an aminoglycoside prote in d iscouragin g further in vesti gati on of th e antibacteri al synthesis inhibitor, ind icating that th e effect on li pid 26 acti vity of the compound seri es T hese studies synthesis is specific and not a conseque nce protein however, suggested, that the bi cycii c nitroimidazoles synthesis inhibition in MTB. As de mo nstrated by PA- might be potenti al antitubercular agents. A seri es of 824, culture and mode ls of anima l in fe tion the NAPs over three hundred ~-s u bs t i tut ed ni troimi dazopyrans possess bacteri c ida l activity again st MTB comparable (NAPs) were synthesized on th e bas is of the structure to that of isoni azid at doses that are ,afe in mice and of CGI- ) 734 I 27 Over 100 of these compounds guinea pi g. PA-824 and the NAPs are also small , possessed substantial anti tubercul ar activity, matching ora lly acti ve molecul es that shouid be amenable to or exceedin g th at ofCGI- I 734 I. iarge-scale production, making them practi cal a nd T he acti ve compounds lacked th e mutageni c it y. attractive candidates fo r the c linical development of a Structure activi ty re lationship studies foc usin g on new antitubercul ar therapy. In add iti on, activi ty antitubercul ar activ ity revealed substanti al vari ety in again st mutidru g-resisitant tubercul osis and the tol erated substitue nt s at C3, but optimal activity demonstrable acti vity by PA-824 against sta ti c MTB was achieved with lipophilic groups. The could offer significant potenti a! for reduc in g th e stereoche mi stry at C3 was important fo r activity, as duration of therapy over current antitubercul ar . · "7 therapies that target on Iy growIn g organlslll s- . References Nakamura S, Structure o/" azomycin , a ne w ant ibiotic, P,'wr/ll BIIIl (Japan), 3 ( 1995) 379. 2 Casar C & 1ulon L, AC li vile dcp(hidrx y-2'-ethyl)- I-methyt- 3·ni tro-5-imidazoles (8823 RP) vi s- · '- vi s de ~ . infections ex peri me nt ates a Tri eomonns vagin alis, Ann !I/st Pasteur, 9(, ( i 959) 238. 3 Martin dale, The comptele drug reference, 32,,<1 ed, edited by CGI- ! 734 1 PA- 824 K Parfitt (Pharmaceu ti cal Pres s. London ; 1909, p. 585 . KAPOOR el ai.: MEDICINAL SIGNIFICANCE OF NITROIMIDAZOLES 665

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