INTRODUCTION:

Tuberculosis is the most prevalent communicable infectious disease on earth and remains out of control in many developing nations. It is a chronic specific inflammatory, infectious disease caused by Mycobacterium tuberculosis in humans. Each year, approximately 2 million persons worldwide die of tuberculosis and 9 million become infected¹.

In 2017, 10 million people fell ill with TB, and 1.6 million died from the disease (including 0.3 million among people with HIV). Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. WHO estimates that there were 558 000 new cases with resistance to rifampicin – the most effective first-line drug, of which - 82% had MDR-TB. Globally, TB incidence is falling at about 2% per year. This needs to accelerate to a 4–5% annual decline to reach the 2020 milestones of the End TB Strategy².

Among the two classes of TB which includes Inactive TB, which is found very common in people over the word and other one is Active TB which can spread to others as well as can make people sick from week to over the years³. Other Than this TB can also be classified as Pulmonary Tuberculosis, which occurs mainly in lungs and affect upper part of lung. Another is extra pulmonary Tuberculosis, which occurs outside the respiratory tract and affect other parts of human body⁴.

Figure-1: New TB cases with MDR/RR-TB as per WHO⁹

Tuberculosis is not only affect respiratory tract and organs but it also lead to some of the immunological and biological changes, one of the studies had found, a marked rise (P <0.05) of liver enzyme e and some renal parameters concentration and significant decline (p<0.05) of serum Creatinine concentration in TB patients were reported in comparison with normal people⁵. RNTCP (Revised National Tuberculosis Control Programme) follows DOTS (Directly Observed Treatment, Short course) strategy to control TB. In one case study which is based on collection of RNTCP charts of over hundred cases were done in which different age groups from the hospital were identified and their reasons for non-compliance of patients were observed. It concludes that HIV patients are more prone to TB infection due to abnormal depression of immune system. The people who is suffering from malnutrition is also very prone to TB infection, Causes of malnutrition includes Gastroenteritis, HIV, poverty and financial challenges⁶.

With regards to all these health concerns major need to establish a new and effective treatment for tuberculosis major challneges include resistance to current therapy was developed known as Extensive Drug Resistance (XRD-TB). Major causes of such Resistance includes Use of streptomycin in hospitals which is well tolerated by M. Tuberculosis, Multiple resistance determinants and Misused antibiotics. In such cases we need to change method of prescription and way of therapy and find new effective drugs⁷. Along with this use of current drug therapy in geriatric patients is a major cause of Acute Kidney Injury (AKI), which was found in recent studies. In age group of 68 years, AKI was developed within two months of use of anti-tubercular therapy⁸.

Figure-2: Pathophysiology of TB: inhalation of bacilli (A), containment in a granuloma (B), and breakdown of the granuloma in less immune competent individuals (C)¹.

Table 1: Current available treatment for Tuberculosis with mechanism First Line¹⁰

First Line Drugs
Sr. No.	Drug	MIC (mg/ml)	Mechanism of action
1	Isoniazid (H)	0.02-0.2	Inhibition of Mycolic acid synthesis and Other Effects
2	Rifampicin (R)	0.05-0.5	Inhibition of RNA synthesis
3	Pyrazinamide (Z)	10-100 (in acidic pH)	Converted into pyrazinoic acid, leads to disrupts membrane potential and interferes with energy production
4	Streptomycin (S)	1.0-8.0	Inhibition of protein Synthesis
5	Ethambutol (E)	1.0-5.0	Inhibition of arabinogalactan Synthesis

Table 2: Current available treatment for Tuberculosis with mechanism Second Line¹⁰

Second Line Drugs
Sr. No	Drug	MIC (mg/ml)	Mechanism of action
1	Flouroquinolones	0.5-2.0	Inhibition of DNA Synthesis
2	Kanamycin/ Amikacin	1.0-4.0	Inhibition of Protein synthesis
3	Capreomycin/ viomycin	2.0-4.0	Inhibition of Protein synthesis
4	Ethionamide	2.5-10.0	Disrupts cell wall Biosynthesis
5	Para-aminosaylicylic acid	0.5-8.0	Inhibition of folic acid and thymine nucleotide metabolism
6	D-Cycloserine	1.5-40.0	Inhibition of peptidoglycan synthesis in cell wall.
7	Clofazimine	0.01-0.25	Production of reactive oxygen species, Inhibition of energy production, Membrane Disruption

Table 3: Novel Drugs for Tuberculosis with mechanism¹⁰

Sr. No	Drug	Drug Class	MIC (mg/ml)	Mechanism of action
1	Bedaquiline (TMC207)	Dihydroquinoline	0.03-0.125	Inhibition of ATP Synthesis
2	Pretonamide (PA-824)	Nitroimidazole	0.015-0.25	Inhibition of Mycolic acid synthesis, Production of relative nitrogen species
3	Delamanid (OPC-67683)	Nitroimidazole	0.006-0.24	Inhibition of Mycolic acid synthesis, Production of relative nitrogen species
4	SQ109	Ethylendiamine	0.16-0.63	Inhibition of Mycolic acid synthesis
5	Linezolid	Oxazolidinone	0.25-1.0	Inhibition of protein synthesis

(MIC-Minimum Inhibitory Concentration)

First and second line drugs are well described in Table-1 and Table-2 respectively, with MIC and mode now major drawback of these drugs is resistance there are two types of major resistance observed in Anti-TB drugs which are challenges as well as the reason for new drug research for Anti-TB. Multi Drug Resistance TB (MDR TB) is described as strains resistance to Isoniazid and Rifampicin, practically incurable by First line drugs and other is Extensive Drug Resistance (XDR TB) is described as strains are resistance to any flouroquinolines, and at least one of three second line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance¹¹.

From Novel drugs described in Table-3, Nitroimidazole class of drugs which shown the greater potency against M. tuberculosis (Mtb) strains compared to other class, which make them to consider as leading class to be researched as novel Anti-TB drugs. In this review article this class of drugs described with full extension.

To identify novel agents for TB one docking study was carried out using fatty acyl CoA synthetase of M. tuberculosis by CPH model server, using pyrazinamide as a reference standard, docking of ligand with enzyme achieved and best ligand found was 2-pyrazinloyl guanidine for further research¹².

To novel anti tubercular drug one more research was done on pyrazole derivative as 14α-demethylase inhibitors involved in cell wall synthesis, they compound in which pyrazole coupled with benzimidazole shown the highest anti-TB activity due to high electronegativity, High lipophilicity and High Molecular weight. This study concluded that molecules with all these three properties can be good anti-TB drug for future¹³.

Nitro Imidazole: A Novel Anti-TB Class:

Nitroheterocyclic compounds have a wide variety of applications, ranging from food preservatives to antibiotics. Nitroimidazoles have therapeutic uses as anaerobic antibacterials and antiprotozoal agents. 5-nitroimidazoles are a well-established group of antiprotozoal and antibacterial agents¹³. Nitroimidazole in fusion with peperazine derivatives was synthesized, had shown excellent Anti-inflammatory activity in in-vitro, using HRBC membrane stabilization method and in-vivo anti-inflammatory activity by carrageenin-induced rat paw oedema model at 20 mg/kg body weight using diclofenac and ibuprofen as standard drugs¹⁴. In one study Nitroimidaole derivatives are found potent antifungal and antibacterial, Researchers had synthesized novel Schiff’s base of 4/5-nitroimidazole and evaluated their Anti-microbial activity against Bacillus subtilis, Pseudomonas aureus using cefixime as standard drug and antifungal activity against Aspergillus niger, Candida albicans, Aspergillus flavus using Clotrimazole as standard drug by agar well diffusion assay method. Synthesized molecules had shown moderate to poor antimicrobial activity, so it need to be investigate further¹⁵.A series of nitroimidazole derivatives have been reported as presenting an outstanding antituberculosis activity against an MDR-TB clinical isolate. Derivatives of 2-Nitroimidazole substituted at 1 and 5 position were found not only to be moderately active against Mtb, but also shown activity against many other organisms¹⁶. 2-nitroimidazoles have reduce potential approximately 150 mV higher than the 5- nitroimidazoles and are, therefore, readily reduced relative to 5-nitroimidazoles. It is to be noted here that, in general, the nitroimidazoles require bioreductive activation for their cidal activity. Nitroimidazole derivatives with lower reduction potential can selectively tap into the redox system of the microbe (as opposed to mammals) and produce cidal activity specific to the microbe¹⁷. Thus, it became increasingly difficult to exploit the structure–activity relationships (SARs) of the 2-Nitro series, due to their reduction by mammalian enzymes, and interest in anti-infective research gradually shifted towards other 4- and 5-nitroimidazole derivatives. These compounds were not mutagenic and showed potent bactericidal activity against replicating and static Mtb, including multidrug-resistant strains¹⁸.

Nitroimidazole as Anti-TB:

CGI-17341

IUPAC Name: 2-ethyl-6-nitro-2, 3-dihydroimidazo [2, 1-b] [1, 3] oxazole

This Chemical entity was developed by Novartis. In 1989, researchers at Ciba-Geigy reported the discovery of a bicyclic nitroimidazooxazole, (CGI 17341), possessing favorable in vitro activity and in vivo efficacy¹⁹. CGI-17341 is an orally active representative of the 5-nitroimidazole series of antimicrobial agents. At concentrations ranging from 0.1 to 0.3 micrograms/ml, CGI 17341 inhibited the drug-susceptible and multi-drug-resistant strains of Mycobacterium tuberculosis. CGI 17341 had no cross-resistance to isoniazid, rifampin, streptomycin, or Ethambutol. CGI 17341 is a promising and novel antituberculosis compound with potent in vitro and in vivo activities²⁰. CGI-17341, which had an in vitro MIC value of 0.32 μM and an in vivo ED50 of 7.7 mg/kg (effective dose of compound at which 50% of mice infected with Mtb survived) was found to be active against ten clinical isolates and several drug resistant Mtb with MICs of 0.43– 1.6 μM. Treatment of mice infected with Mtb after 11 and 12 days post infection with CGI-17341 showed activity of this compound at a dose of 80 mg/kg for 2 months²¹.

Figure-3: Scheme for synthesis of CGI 17341²²

Ashtekar R, et al. in 1993 had done various in vivo and in vitro activities of CGI-17341 against Mtband after his research he had found that it had no cross resistance with Isoniazid, Streptomycin, Rifamicin or Ethambutol. It is very potent to conventional drugs in terms of MIC, so it becomes the very promising compound and clues for further research with potential activity against Mtb²³. Stover et al. in 2000 discovered that a nitroimidazo class of small molecules is very good candidate for latent TB treatment, as they mainly worked by inhibiting synthesis of protein and cell wall lipid and also exhibited bactericidal activity against both replicating and static Mtb²⁴. Hirofuni S et al. in 2006 prepared various optically active derivatives, which were substituted at the 2-position with the various phenoxymethyl group and methyl group and investigated in vitro and in vivo activity against Mtb strains. Among it some displayed excellent in Vitro activity against both drug-susceptible and drug-resistant strains of Mtb²⁵.Manjunatha HM et al. in 2006 identified the protein that is involved in the Resistance to these nitroimidazo-oxazine. As this class of drugs are pro drug which are activated by reduction by the specific glucose 6-phosphate dehydrogenaze (FGD1) or its dezaflavin cofactor F₄₂₀²⁶. In preclinical studies found that this Nitroimidazole agent is Mutagenic in nature, so it was terminated from further clinical trials, but it proposes the strong rationale for development of new Nitroimidazole derivative with modification for TB treatment^{20, 23}.

TBA-354

IUPAC Name: (6R)-2-nitro-6-({6-[4-(trifluoromethoxy) phenyl]pyridin-3-yl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

This Chemical entity was first put on Phase-1 clinical trial by not-for profit organization TB alliance, University of Auckland in 2015²⁷. TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB²⁸. TBA-354 is a promising new antituberculosis nitroimidazole derivative that was tested for pharmacokinetic profile and activity against Mtb. The effects of TBA-354 were compared against PA-824 and delamanid, two other nitroimidazole derivatives proven effective against the bacteria. The researchers synthesized 170 compounds in an effort to find a drug effective against TB²⁹.

Figure-4: Scheme for Synthesis of TBA-354²⁸

Tanaseen R. et al. in 2015 had done studies of murine models to find potency of TBA-354 compared to other drugs of same class PA-824, In his studies, he found that TBA-354 have superior in-vitro 5 to 8 times more potent in monotherapy as well as in combination with Bedaquline and Pyrazinamide, sutezolid and/or clofazimine 2 to 4 times potent than PA-824³⁰. Upton AM et al. in 2017 had done In-vitro and In-vivo activities against M. Tuberculosis, TBA-354 are a potential candidate to become second generation Nitroimidazole anti-TB agent as it shows exceptional efficacy against chronic murine tuberculosis, it has high bio-availability, low-risk of drug-drug interaction and maintains its activity against MtbH37Rv isogenic mono resistant strains³¹. In 2016 National Library of Medicine, USA in reference to information provided by Global Alliance for TB drug development was carried out Phase 1 study to evaluate the safety, Tolerability and Pharmacokinetics of TBA-354 in Healthy subjects with placebo control and they had found that it have mild toxicity on Subjects so it leads to discontinuation of clinical trial of this agent and it is removed from clinical pipeline for more development to reduced toxicity by Originator, TB alliance^{32, 33}. Ntshangase S et al. in 2017 had done studies to explain neurotoxicity of TBA-354 with the help of Mass spectrometry imaging. LCMS/MS investigation of plasma pharmacokinetics and brain distribution of TBA-354 after single dose administration drug reaching C_maxat the 6h post dose and showed a time-dependent drug distribution, with highest concentration mainly in neocortical region of the brain, this describe the possible failure of the drug in clinical trial³⁴.

PA-824

IUPAC Name: (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

Generic name: Pretomanid

PA-824 or recently approved as Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines, which is in Phase-II clinical trial. Pretomanid has been clinically evaluated and developed by TB Alliance, a not-for-profit product development partnership dedicated to the discovery and development of new, faster-acting and affordable tuberculosis medicines in with collaboration with Novartis, Originator. It has been studied in 20 clinical trials alone or in combination with other anti-TB drugs. Since TB Alliance began development of pretomanid in 2002, it has been administered in a clinical trial setting to more than 1,200 people in 14 countries^{35, 36}. Pretomand will continue to be referred to as “Pa” in regimen abbreviations, such as BPaMZ. The “preto” prefix of the compound’s name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drug’s development took place. The “manid” suffix is used to group compounds with similar chemical structures³⁷. On March 8, 2019 in the Press release of TB alliance announced that New Drug application (NDA) for PA-824 was accepted by US-FDA as a part of regimen in combination with bedaquiline and linezolid, for the treatment of extensively drug-resistant (XDR) TB, treatment intolerant multidrug-resistant (MDR) TB, and treatment non-responsive MDR-TB³⁸.

Figure-5: Scheme for synthesis of PA-824³⁹

PA-824 was a nitroimidazole class of drug which was developed in structural similarity with CGI-17341 and OPC-67683. In 2008, as this was in clinical phase, Mechanism of action PA-824 was quite unclear, it was assumed that it was act by generation of radical having non-specific toxic effects and it also show mycolic acid and protein biosynthesis mechanism, this kind of interesting mechanism lead further clinical development of PA-824⁴⁰. Kim et al. in 2009 describes the structure activity relationship (SAR) via synthesis of many 5-nitroimidazole derivative (PA-824), active against both aerobic and anaerobic Mtb and compared it with 4-nitroimidazole derivatives (Metronidazole), active against only aerobic Mtb. He found that bicyclic oxazine, the lipophilic tail and 2-poistion oxygen is very essential for aerobic activity, which was missing in 4-nitroimidazole derivatives⁴¹.

Manjunatha et al.in 2009, describe that PA-824 have inhibitory activity against both actively replicating and hypoxic non-replicating Mtb. It is a pro-drugs activated by a deazaflavin (cofactor F420) dependent nitroreducase (Ddn). They had done transcription profiling and concluded that it had shown up of the up regulation of fasI gene as well as many genes in the fasII operon; along with efpA and iniBAC operon, which are involved in cell wall synthesis inhibition. This transcriptional profile was very similar to cytochrome c oxidase-specific inhibitors like potassium cyanide, respiratory poisoning. Metabolite profiling of PA-824 and its analogues by Ddn, we have recently shown that these bicyclic nitroimidazoles act as [NO] donors, and that NO release from various PA-824 derivatives correlated well with the anaerobic killing of Mtb. Thus PA-824 acts as a “suicide bomb” releasing toxic NO within mycobacterial cells and NO possibly react with cytochromes/cytochrome oxidase to interfere with the electron flow and ATP homeostasis under hypoxic non-replicating conditions⁴².

Thompson et al. in 2009, had synthesized many bicyclic nitroheterocycles and compare it with one electron reduction potential (E1) of PA-824, to evaluate the effect of this parameter on biological activity. These compounds have a wide range of E1, ranging from -570mV to -338mV, compared with -534mV of PA-824,correlated with s_m of heteroatom of adjacent six membered ring, with such wide span of E1, shown the same level of potency which suggested that E1 is not a major factor of activity by reductive activation but activation by reduction pathway is determined by the substitution at 2-position of 4-nitroimidazole ring⁴³.

Somasundaram et al. in 2013, had analyzed the activity of PA-824 for latent tuberculosis in anaerobic condition and compared with Rifampicin (RFP) and Pyrazinamide (PZA). She had identified novel agents which are active against A76E mutation, lead to mutation of Ddn receptor, responsible for resistance of PA-824 by docking studies. She had found that 12.5mg/ml has enhanced bactericidal activity compared to the RFP and PZA, by docking studies, she had found that PA-824 conjugated with Moxifloxacin has a highest binding affinity with mutant Ddn receptor⁴⁴.

Rakesh et al. in 2016, had synthesized PA-824 oxazolidinone hybrids as PA-824 have poor solubility and high protein binding, whereas oxazolidinine derivative lineazolid shown good solubility and antiTB activity. From studies, he had found that in vitro physicochemical properties were improved, but hybrids have less in vivo efficacy compared to PA-824 as lipophilic tail is missing⁴⁵.

Thompson et al. in 2017, had synthesized and studied to confirm the structural feature of PA-824, that 3-nitroimidazole derivative of PA-824, confirmed by the X-Ray crystal structure, was totally inactive compared to 2-nitroimidazole (PA-824), whereas the second byproduct that is 3’methyl substituted in lipophilic chain, adjacent to -OCF₃ of PA-824 was 8-times more potent in aerobic assay⁴⁶.

OPC-67383

IUPAC Name: (R)-2-Methyl-6-nitro-2-((4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)phenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazole

Generic name: Delamanid

Brand Name: Deltyba^TM (Otsuka Pharmaceutical Development and Commercialization, Inc.)⁴⁷

OPC-67683 (also known as delamanid) is an experimental drug that has shown potent activity against drug-resistant and drug-susceptible TB, currently in Phase-III clinical trial. It was studied and produced by Otsuka Pharmaceutical Development and Commercialization (Osaka, Tokyo, Japan). OPC-67683 belongs to a class of drugs called nitroimidazoles⁴⁸. Delamanid, a major representative of this class, was clinically evaluated, phase II, in patients with pulmonary tuberculosis for safety, efficacy and Pharmacokinetics in 2006, with collaboration with Otsuka Frankfurt Research Institute GmbH, Germany. This study results show improvement in patients with which suggest it have bactericidal activity in primary cases, better than first line drug in low dose⁴⁹. The medication was not readily available globally in 2015. It was believed that pricing will be similar to bedaquline, which for six months is approximately US$900 in low income countries, US$3,000 in middle income countries, and US$30,000 in high income countries. As of 2016 the Stop TB Partnership had an agreement to get the medication for US$1,700 per six month⁵⁰.

Figure-6: Scheme for synthesis of OPC-67683⁵¹

Matusumoto et al. in 2006, had done anti-TB screening of OPC-67683 in different Mtb strains, from his research, he found that OPC-67683 is a very promising agent against different Mtb stains, it had shown very good MIC 0.006-0.24 mg/ml in vitro and highly effective in-vivo in low dose, The combination of OPC-67683 with Rifampicin (RFP) and Pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2) of viable TB bacilli in the lung in comparison with the standard regimen of first line drugs. OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, so it had set strong rational to be used in combination with other drugs such as anti-retrovirals that induce or are metabolized by cytochrome P450 enzymes⁵².

Sliu et al. in 2007, had done research on bactericidal activity of OPC-67683 against in-vitro drug tolerant models of Mtb strains, after study, he had selected 4 isolated from the 16 surveyed, based on delayed killing by isoniazid (INH) and OPC-67683, unlike INH and RFP, OPC-67683 shows concentration dependent effect, at highest tested dose level (1.0mg/ml), were superior to INH and similar to RFP. These results provide a solid background for the study of the drug intolerant human patients⁵³.

Diacon et al. in 2011, after clinical study of OPC-67683, researched on the Early Bactericidal Activity of this drug in pulmonary tuberculosis patients. He had done this study of 48 patients for 14 days, which were randomly assigned to receive different doses of delamanid daily. Colony forming unit (cfu) was counted on agar plates from the overnight sputum collection to calculate EBA, defined as a fall in log₁₀cfu/ml sputum/day. After studying average EBA of all doses combined (0.040± 0.056 log₁₀ cfu/ml sputum/day), with patients receiving 300mg dose shown highest decline (80%). It was well tolerated without significant so it further needed to study for pharmacokinetics and Anti-TB activity⁵⁴.

Geler MT et al. in 2012, checked activity of OPC-67683 in Multidrug resistant pulmonary tuberculosis (MDRPT) patients, he had assigned 481 patients with MDRPT to receive delamanid at different doses with placebo for 2 months with a background drug regimen developed according to WHO guidelines. After studying patients who had received 100mg delamanid and 200mg of delamanid plus background drug regimen had 45.4% and 41.9% sputum-culture conversion respectively. This study concluded that delamanid will improve the therapy option for MDR TB patients⁵⁵.

Skripconika V et al. in 2013, had done another study of 461 patients to check mortality of OPC-67683 with an optimized background regimen by WHO. Favorable results were seen after study in patients who received delamanid with an optimized regimen for ≥ 6 months than the patients who received for ≤ 2 months. The mortality rate was also decreased to 1.0% in long term treatment than short treatment with good therapeutic effect in both XDR TB and MDR TB. OS this study conclude that the delamanid is a very good choice of drug in combination with other drug therapy for patients with less mortality and good efficacy in XDR TB and MDR TB⁵⁶.

Caminero JA et al. in 2015, recommended delamanid as a third group drug for treatment MDR TB and XDR TB in combination with bedaquline. Bedaquline active against both active and dormant bacilli, but it’s shown adverse effects as monotherapy, QTc interval increase in ECG, and it is also shown cross-resistance with other TB drugs, Delamanid shown no such cross resistance and also have a common side effect. So WHO recommended this combination therapy for first 6 months only with background optimized regimen⁵⁷.

Sotugui et al. in 2015, had written a detailed review on delamanid in which he explains its mechanism of action very clearly that it acts via inhibition of Mycolic acid synthesis in Mtb and it does not have any mutagenic property. Delamanid also has ability to negatively modify cell wall metabolism, which is good for direct anti-TB activity, but it also facilitates penetration of other drugs⁵⁸.

Stinson K et al. in 2016, had done research to confirm MIC against Mtb in clinical isolates and critical concentration. For this study clinical isolates collected from previous clinical trials which was conducted in Europe, South Africa and outside clinical trial with global clinical trial. From his study, he found MIC in delamanid and that is MIC₅₀ is 0.004µg/ml and MIC₉₀ is 0.012µg/ml, and critical concentration was proposed 0.2 µg/ml to define susceptible and resistant isolates based on the distribution of MIC and available pharmacokinetic data⁵⁹.

CONCLUSION:

MDR TB and XDR TB are one of the main reasons for mortality in the world and there is an urgent need to develop newer drugs to cope up with these. Nitroimidazoles are one of the emerging class of the drug for MDR TB and XDR TB. Research had been conducted on this since late 90s and still it is going on. Started with some failure like CGI-17341, excluded due to mutagenicity, but it sets a strong rationale that this class of drugs can be potent Anti-TB drugs. This lead to development of Protenamid (PA-824) and Delamanid (OPC-67683), which are becoming excellent clinical candidates for treatment of XDR TB. Recent failure with TBA-354 is its neurotoxicity and may lead to conclude that lot of research will be carried out in this class to develop newer agents which can become the potential treatment for TB patients worldwide.

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Received on 23.09.2019 Modified on 27.10.2019

Research J. Pharm. and Tech. 2020; 13(7): 3425-3432.

DOI: 10.5958/0974-360X.2020.00609.5