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32.Priyanka B. Gorde , Kalyani Kale, Manish A. Raskar

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32.Priyanka B. Gorde , Kalyani Kale, Manish A. Raskar Human Journals Review Article March 2021 Vol.:20, Issue:4 © All rights are reserved by Priyanka B. Gorde et al. A Systemic Review on Oxazolidinones as Anti-Tubercular Agents and Antibacterial Agent Keywords: Anti-tubercular agents, Oxazolidinone, Linezolid, Sutezolid, SAR ABSTRACT Priyanka B. Gorde *, Kalyani Kale, Manish A. TB drug development pipeline represents varied structural Raskar classes of molecules. Oxazolidinones represent synthetic Department of Pharmaceutical Chemistry, Dr. antibacterial agents with a unique mechanism of action Vithalrao Vikhe Patil College of Pharmacy having a wide spectrum of activity, oral bioavailability, and Ahmednagar, India. well-established SAR. They act by inhibiting translation at the initiation phase of protein synthesis. Linezolid was the Submitted: 09 February 2021 first oxazolidinone to reach the market in the year 2000 for Revised : 28 February 2021 the treatment of methicillin-resistant staphylococcal and Accepted: 20 March 2021 vancomycin-resistant enterococcal infections. Oxazolidinones have shown very good anti-mycobacterial activities. Several oxazolidinones are currently in development for their possible use in TB therapy. Oxazolidinones are classified based on C-ring modifications. www.ijppr.humanjournals.com DuP-721 was the first oxazolidinone having good anti-TB activity. Linezolid, sutezolid and AZD5489 are in clinical devel- opment. Several other C-ring modifications have shown promising results. The usefulness of these oxazolidinones in drug-resistant TB is already established. Toxicity, especially myelosuppression, has been an im- important limiting factor for their development. Citation: Priyanka B. Gorde et al. Ijppr.Human, 2021; Vol. 20 (4): 448-478. 448 www.ijppr.humanjournals.com INTRODUCTION Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) [1], accounts for the death of 1.5 million people; 360, 000 of whom were Human Immunodeficiency Virus (HIV) positive and 9.0 million new cases in 2013 [2]. Latent TB infection in the Mtb infected (LTBI) people increases the possibility of reactivation of this deadly disease [3,4]. The current year 2015 marks the 132nd anniversary of Robert Koch’s discovery of the tubercle bacillus Mtb [5]. Most of the first-line drugs were discovered in the 1950s and 1960s. For nearly a half-century, TB patients lacked new drugs to be available for treatment until Bedaquiline was launched at the end of 2012, which was approved to treat multidrug-resistant tuberculosis (MDR-TB, resistant strains to isoniazid (INH) and rifampicin, RIF) [6]. The development of drug resistance, rise of multi- and extensively- drug resistant TB (MDR-TB and XDR-TB: more insusceptible to any fluoroquinolone and one of three injectable drugs) strains, and the long duration required for the treatment of TB, make it imperative to develop novel leads against TB. The devastating effect of HIV co-infection has led to an urgent need for the development of new, fast-acting, and more efficient anti-mycobacterial drugs. An ideal drug candidate is required to act on a novel target and also be effective against the resistant Mtb strains [7]. Current anti-TB drugs target bacterial cell wall synthesis, protein synthesis, and fatty acid synthesis [8]. The therapeutic regimen for the treatment of TB involves first-line drugs such as isoniazid (INH), rifampicin (R), pyrazinamide (Z), ethambutol (E), streptomycin (S), and rifabutin (Rfb), second-line drugs such as kanamycin (Km), amikacin (Amk), capreomycin (Cm), viomycin (Vim), ciprofloxacin (Cfx), levofloxacin (Lfx), ofloxacin (Ofx), para-aminosalicylic acid (Pas), D-cycloserine (Dcs), teridizone (Trd), ethionamide (Eto), prothionamide (Pto) and thioacetazone (Thz), and third-line drugs such as clofazimine (Cfz), amoxicillin plus clavulanate (Amx/Clv), linezolid (Lzd) in combination regimens to treat MDR-TB or XDR-TB [2,9,10]. Directly observed treatment short-course strategy (DOTS) provides a cure rate of > 95% for the treatment of drug-sensitive TB with initial treatment for two months with four drugs (INH, R, Z, and E) and subsequent four months treatment with two drugs (INH and R). Drug- resistant TB requires the use of second-line toxic drugs for a longer duration (18-24 months or more) of time. The coinfection of TB with HIV further complexes the problem leading to morbidity and mortality [11]. The currently employed drugs have many Citation: Priyanka B. Gorde et al. Ijppr.Human, 2021; Vol. 20 (4): 448-478. 449 www.ijppr.humanjournals.com potential side effects viz. Z causes hepato- toxicity and gout because of a decrease in uric acid secretion in urine, INH causes peripheral neuropathy in fast acetylators and hepatotoxicity in slow acetylators, RIF causes orange discoloration of body fluids such as lymph, saliva, lacrimal fluid, sputum, sweat, and urine because of dye characteristics and E causes optical neuritis or retrobulbolar neuritis, aminoglycosides causes ototoxicity and nephrotoxicity [8]. In total, none of the anti-TB drugs is devoid of hazardous side effects. This, in deed, enhances the need for the development of novel chemical entities and novel anti-tubercular agents. Apart from these, several classes of molecules are in different stages of development (Table 1) providing some promise [10]. This review highlights the progress made by oxazolidinones a new structural class of anti- biotic. First oxazolidinone linezolid was approved in the year 2000 for the treatment of methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections [12]. Since then there is spurred interest in research in this area [13,14]. Considering their promising activity against M. tuberculosis the search for molecules as potential anti-TB agents is pursued. This review highlights the developments in oxazolidinones as anti-TB agents, the only review highlighting these developments appeared in 2006 [15]. ANTI-TB DRUG PIPELINE New chemotherapeutics active against multidrug-resistant M. tuberculosis are urgently needed. Despite the urgent need for new anti-tubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new or novel targets will be required. The Novel Chemical Entities (NCEs) which have distinguished potential to be drug candidates for the treatment of TB are represented in (Table 1) with their chemical class, mode of action, in vitro activity, and current clinical status. These NCEs are represented in (Fig. 1) with their trivial names. TB Alliance with the help of the University of Auckland and University of Illinois- Chicago has developed nitroimidazoles such as PA-824 (1) and delamanid(OPC67683) (2) a new drug class for drug-sensitive and drug-resistant Mtb [16]. TBA-354 (3) is a next-generation nitroimidazole for TB treatment with demonstrated advantages over the first-generation compounds and entered clinical testing in 2015 [17]. Currently, in phase III clinical trial treatment of drug-sensitive TB in four months, a possible replacement of Citation: Priyanka B. Gorde et al. Ijppr.Human, 2021; Vol. 20 (4): 448-478. 450 www.ijppr.humanjournals.com E/INH by fluoroquinolone moxifloxacin (4) and E by fluoroquinolone gatifloxacin (5) is being established [18]. Bedaquiline (7) is a diarylquinoline class anti-TB drug approved by the US FDA for the treatment of MDR-TB [19]. It has been recognized as the first anti- TB drug to interfere with bacterial energy metabolism [20]. SQ109 (8) a 1,2- ethylenediamine derived from E through combinatorial synthesis is under clinical development [21]. A phase IIa clinical trial for LL3858 (10) a pyrrole derivative developed by Lupin Limited has shown the potential for the treatment of tuberculosis [22]. Linezolid or PNU-100766 (11), sutezolid or PNU-100480 (12), and AZD5847 (13) are the only oxazolidinones which have reached phase II of the clinical trial. AZD5847, a next-generation oxazolidinone, is having bactericidal action and has completed Phase I clinical trials [23]. Rifapentine has entered in a clinical trial, in 2008 with a view of the evaluation of antimicrobial activity and safety in which several doses of rifapentine are substituted for rifampin [17]. BDM31343 (15) has been evolved as an emerging drug candidate among 1,2,4-oxadiazoles and is currently under preclinical trial [24]. BTZ043 (16) has shown excellent whole cell-based activity (1 ng/mL) among nitrophenyl derivatives with a completely novel mechanism of action [25]. Various diversified NCEs too have the potential to become anti-mycobacterial drugs such as PBTZ169 (18), TBI- 166 (19), CPZEN-45 (20), SQ641 (21), Q203 (22), and 23 are under preclinical trial. Other NCEs such as 377790 (24), C215 (25), A039 (26), and AU1235 (27) have been identified as active anti-tubercular hits, and their respective biological targets are also well elaborated [26,27]. Table No. 1: Different chemical classes of NCEs for TB in clinical pipeline. In vitro Clinical Chemical Drug Activity Entry Mode of action Status [17] Refs. Class Candidate (MIC) Bactericidal action by 0.015-0.25 PA-824 (1) III [29] intracellular NO release[28] µg/mL TBA-354 (3) Same as that of PA 824 0.004 µM I [30] Delamanid 0.006-0.024 1 Nitroimidazole Inhibits mycolic acid (OPC67683) (2) µg/mL III [31] synthesis Citation: Priyanka B. Gorde et al. Ijppr.Human, 2021; Vol. 20 (4): 448-478. 451 www.ijppr.humanjournals.com Table 1) contd…. In vitro Clinical Chemical Drug Activity Entry Mode of action Status [17] Refs. Class Candidate (MIC) Moxifloxacin Inhibits
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