**Bedaquiline or TMC207**

Bedaquiline is a diarylquinoline and used bactericidal. Bedaquiniline involves blocking the proton pump of ATP synthase of *Mtb* then depletes the energy demand of both replicating and nonreplicating (dormant) mycobacteria and at the result in cell death [66, 67].

### **Delamanid or OPC 67683**

Delamanid is a dihydro-nitroimidazooxazole derivative and activated by deazaflavin-dependent nitroreductase enzyme (Rv3547). It acts by interrupting the mycobacterial cell wall component synthesis. Delamanid inhibits the methoxy- and keto-mycolic acid synthesis which is a vital component of the *Mtb* cell wall. It is active against both growing and nongrowing mycobacteria [68, 69].

### **PA-824**

PA-824 is a nitroimidazole derivative and it activated by deazaflavin-dependent nitroreductase like delamanid. Mechanism of action is not clearly konown but it could be described as its activity in replicating and non-replicating mycobacteria. In aerobically replicating cell PA-824 interrupts mycolic acid synthesis by the collecting of hydroxymycolates instead of ketomycolates [70, 71]. In hypoxic non replicating mycobacteria, PA-824 release nitric oxide (NO) that interferes with cytochrome oxidase to disrupt the energy metabolism of the cell wall [72].

### **SQ-109**

SQ-109 is an ethambutol analog and its mechanism of action is not known. It has no inhibitory activition against the secreted Ag85 mycolyltransferase. Rather SQ-109 causes collection of trehalose monomycolate a precursor of trehalose dimycolate by obstructing accumulates of mycolic acids into the *Mtb* cell wall core [73].

### **Antitubercular drugs with the new and different moiety**

To investigating useful drug candidate's currently in two major categories: Novel chemical entity and compounds instigating from existing relatives of currently used drugs, where novel chemistry is used to optimize the new compounds.

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Nitroimidazopyrans and Nitroimidaoxazoles derivatives**

In this series, the lead molecules are CGI 17341 and PA824/PA1343 and inhibit the cell wall synthesis. However, two key areas of concern also require to attendpossible mutagenicity resulting from the presence of a nitro group, and the chance for the development of drug resistance. The latter is encouraged by the reality that the nitroimidazoles induce a high rate of mutation [2–4], leading to uncertainties that this might cause the appearance of MDR bacteria. Since the drugs will certainly be used in combination therapy [74].

#### *Nitroimidazole PA-824*

**Moxifloxacin**

**Macrolides**

cell death [66, 67].

**PA-824**

**SQ-109**

**38**

drug to shorten TB treatment [62, 63]. **Non-fluorinated quinolones**

are presently being tested against *Mtb* [4].

**New rifamycin derivatives**

**Bedaquiline or TMC207**

**Delamanid or OPC 67683**

anti-TB agent superior to the clarithromycin [4, 15].

resistant strains present cross-resistance to all rifamycin drugs [65].

active against both growing and nongrowing mycobacteria [68, 69].

aerobically replicating cell PA-824 interrupts mycolic acid synthesis by the collecting of hydroxymycolates instead of ketomycolates [70, 71]. In hypoxic non replicating mycobacteria, PA-824 release nitric oxide (NO) that interferes with cytochrome oxidase to disrupt the energy metabolism of the cell wall [72].

by obstructing accumulates of mycolic acids into the *Mtb* cell wall core [73].

**Antitubercular drugs with the new and different moiety**

drugs, where novel chemistry is used to optimize the new compounds.

*In-vitro m*oxifloxacin (MXF) show to kill a subpopulation of tubercle bacilli that not killed by RIF, while the older FQs, (ciprofloxacin) CPX, and (ofloxacin) OFX did not have any major bactericidal effect. The MXF obstructs protein synthesis in gradually metabolizing bacteria through a mechanism that varies from that used by RIF. In mice models, the effect of MXF against tubercle bacilli was comparable to that of INH [59]. In combination with MXF and PZA has been killing the bacilli more successfully than the INH + RIF + PZA combination [60]. The substitution of MXF with INH in the standard drug therapy could relieve a probable antagonism among the presently used drugs [61]. The MXF might be a promising candidate

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

A series of 8-methoxy non-fluorinated quinolone analogs (NFQs) lack a 6-fluorine atom in their quinolone ring distinguishing them from fluorinated quinolone compounds such as GAT and MXF. The NFQs target a broad range of bacteria and they appear to operate preferentially through inhibition of DNA gyrase. The NFQs

The anti-TB effect of the macrolide antibiotics through the synthesis of additional chemically modified analog of erythromycin. Some analog were recognized as

Rifalazil, a semisynthetic RIF, is described by a long half-life and is more effective than RIF and rifabutin against *Mtb* strains [64]. However, high-intensity RIF–

Bedaquiline is a diarylquinoline and used bactericidal. Bedaquiniline involves blocking the proton pump of ATP synthase of *Mtb* then depletes the energy demand of both replicating and nonreplicating (dormant) mycobacteria and at the result in

Delamanid is a dihydro-nitroimidazooxazole derivative and activated by deazaflavin-dependent nitroreductase enzyme (Rv3547). It acts by interrupting the mycobacterial cell wall component synthesis. Delamanid inhibits the methoxy- and keto-mycolic acid synthesis which is a vital component of the *Mtb* cell wall. It is

PA-824 is a nitroimidazole derivative and it activated by deazaflavin-dependent nitroreductase like delamanid. Mechanism of action is not clearly konown but it could be described as its activity in replicating and non-replicating mycobacteria. In

SQ-109 is an ethambutol analog and its mechanism of action is not known. It has no inhibitory activition against the secreted Ag85 mycolyltransferase. Rather SQ-109 causes collection of trehalose monomycolate a precursor of trehalose dimycolate

To investigating useful drug candidate's currently in two major categories: Novel chemical entity and compounds instigating from existing relatives of currently used

The PA-824 is a nitroimidazole derivative and used as anti-TB agent. PA-824 acts mainly as synthesis of cell wall components inhibitor. *In vitro*, PA-824 showed high activity against drug-sensitive and MDR-TB strains, there is no crossresistance with currently used anti-TB drugs. Moreover, PA-824 has shown *in-vitro* bactericidal activity against both replicating and static bacteria [4]. The PA-824 bactericidal effect against nonreplicating bacteria was equivalent to the RIF. Use of PA-824 as monotherapy in mice and cause reduced bacterial counts in the lungs is better than RIF or INH monotherapy. After 12 weeks of treatment with PA-824, RIF, or INH, complete removal of the bacterial load was not getting in any of the treated mice [2–4].

#### *Nitroimidazoles CGI 17341*

The CGI 17341 has substantial potential as anti-TB agent in a preclinical study. *In-vitro* at 0.04 to 0.3 μg/ml, it inhibited both drug-susceptible and MDR-TB strains and exhibited no cross-resistance with INH, RIF, SM, or EBM. *In-vitro* against *Mtb*, its action was similar to that of INH and RIF and higher to SM, norfloxacin, ciprofloxacin, and the oxazolidinone DuP 721. In *Mtb*-infected mice, oral treatment with CGI 17341 on days 11 and 12 after infection resulted in an ED50 of 7.7 mg/kg and showed a significant dose-dependent progress in survival time [75]. These drugs were not mutagenic and showed potent activity against replicating and static *Mtb*, including MDR strains.

#### *Nitroimidazole OPC-67683*

It is mycolic acid inhibitors and interferes with the biosynthesis of the mycobacterial cell wall. *In vitro*, OPC-67683 was exhibited high activity against drugsensitive as well as DR strains with MICs varying 6–24 ng/mL. There is no crossresistance with any of the current first-line anti-TB drugs. Moreover, OPC-67683 exhibited strong intracellular activity against the *Mtb*H37Rv residing within human macrophages and type II pneumocytes. The OPC-67683 is active against *Mtb*H37v and MDR-TB strains *in-vivo* starting from a concentration of 0.03125 mg/body [2– 4]. The OPC-67683 exhibited 6–7 fold elevated activity compared to first-line drugs INH and RIF.

#### **Imidazole Analogues**

Miconazole is a well-known antifungal drug that has been accounted for to have anti-TB activity *in vitro* against *Mtb*H37Ra (MIC 2 μg/ml). It inhibiting replicating bacteria and also has some effect on stationary phase bacilli [88]. Unfortunately, miconazole is not active orally and therefore is little additional interest in progressing TB indication [76].

**Thiolactomycin Analogues**

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

**Mefloquine Analogues**

*Deazapteridines*

**41**

drug halofantrine of lesser cardiotoxicity.

Naturally occurring (5*R*)-thiolactomycin (TLM) exhibits potent *in vivo* activity against many pathogenic bacteria, and *Mtb* [84]. TLM inhibited bacterial and plant type II fatty acid synthases (FAS-II) but not inhibited mammalian or yeast type I fatty acid synthases (FAS-I) [85]. In *E. coli*, it inhibited both β-ketoacyl-ACP synthase I to III and acetyl coenzyme A (CoA): ACP transacylase activities [86, 87]. The TLM was the first example of naturally occurring thiolactone to displayed antibiotic action. The TLM analogs have improved activity against whole cells of pathogenic *Mtb* strains [88]. The TLM analogs act by the inhibition of the mycolate

This has led to the hope that inhibitors of the TLM target enzyme, FAS-II, are potentially important in the treatment of malaria [89], trypanosomiasis, or sleeping sickness [90], and a range of bacterial indications including TB. It also blocks longchain mycolate synthesis in a dose-dependent mode [91]. The TLM is active *in vitro* against an extensive range of strains of *Mtb*, including INH- resistant, although at somewhat high concentrations. For example, complete inhibition of growth on solid media of the strain *Mtb* Erdman is seen at 25 μg/ml. The TLM itself as an anti-TB agent [92] and racemic mixtures, e.g. compounds (**A**) and (**B**), which are accounted

The antimalarial agent mefloquine and its analogs have activity against a range of bacteria including *Mtb* [93]. A series of quinolinemethanol analogs, two compounds, WR-3016, and WR-3017, exhibited potent inhibitory effects in vitro in the *M. avium* complex-1 (MAC) assay with MIC50 values of 1 and 2 μg/ml respectively, compared to 16 μg/ml for mefloquine. Other mefloquine analogs, two enantiomers of mefloquine and might be valuable to test some representative 4-aminoquinoline antimalarials such as chloroquine [94]. Another compound desbutylhalofantrine (**3**) is in progress for its antimalarial activities with an advantage over the parent

Some 2,4-diamino-5-deazapteridine derivatives, SRI-20094 has potent inhibition of MM6 cells infected with MAC strain NJ3440 with a MIC value 0.13 μg/ml. SRI-20094 inhibits the dihydrofolate reductase (DHFR) of the MAC, with an IC50

value 1.0 nM as compared to 4100, 1.4 and 1.0, nM for the trimethoprim,

synthase, an enzyme involves in the biosynthesis of the *Mtb* cell wall.

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

to have superior activity than the parent in inhibiting *Mtb* H37Rv *in-vitro*.

#### **1,2,4-Triazoles**

Various 1,2,4-triazoles have been estimated against *Mtb* H37Rv. Compound (**1**) gave 61% inhibition at 6.25 μg/ml. Other triazole analogs were inactive [2–4].

#### **Imidazo(4,5-c)pyridine compounds**

A series of imidazo(4,5-c)pyridines, one compound (**2**) for common formula (R1, R2 unrevealed)-inhibited *Mtb*H37Rv and other strains with MICs range 0.256– 2.56 μg/ml. Imidazo(4,5-c)pyridines were initially prepared as anti-mitotic agents but in the present work, fewer cytotoxic agents were chosen and found to have anti-TB activity [4].

#### **Diarylquinoline compounds**

Diarylquinolines (DARQs) is structurally unlike both FQs and other quinolines derivatives. The DARQ R207910 is a new class of anti-TB drugs. It has specificity towards mycobacteria as well as atypical species, important in humans such as MAC, *M. kansai,* and the fast-growing *M. fortium* and *M. abscessus* [77]. The anti-TB specific spectrum differs from that of INH, which has very poor activity against MAC. It will be extremely targeted to the treatment of TB infections, mainly targeting the proton pump of ATP synthase [78].

#### *Diarylquinoline TMC207*

Diarylquinoline (DRQ) TMC207 is an exceptionally promising class of anti-TB drugs. About, 20 compounds of the DRQ series have been exhibited a MIC value below 0.5 μg/ml against *Mtb* H37Rv [78]. The most active compound of this class is TMC207 against *Mtb*. The mechanism of action of DRQ TMC207 is different from those of other anti-TB drugs involving a low probability of cross-resistance with accessible anti-TB drugs. The DRQ TMC207 is capable to inhibit bacterial growth against MDR-TB isolates and appears to act by inhibiting the ATP synthase [79], most important to ATP depletion and pH imbalance. Substitutions of RIF, INH, or PZA with DRQ TMC207 hasten activity [80].

#### **Purine Analogs**

The 9-Benzylpurines, with a variety of substituents on 2, 6, and/or 8 positions, have high inhibitory activities against *Mtb*. One compound, carrying trans-styryl or aryl substituents at 6 positions and generally chlorine in 2 positions tends to increase the *in vitro* activity and has MIC of 0.78 mg/mL [81]. The anti-TB activity of 6 arylpurines [82] and 9-sulphonylated or sulphenylated-6-mercaptopurines are also known [83].

#### *Benzylpurines*

The 9-benzylpurines, 2-chloro-4(2-furanyl)-9-benzylpurine was potently inhibited *Mtb* H37Rv *in-vitro* with a MIC value of 0.78 μg/ml with low cytotoxicity towards VERO cells (IC50 value-8.1 μg/ml) selectivity index (MIC/IC50) of 10.4 [4]. *Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Thiolactomycin Analogues**

**1,2,4-Triazoles**

TB activity [4].

**Imidazo(4,5-c)pyridine compounds**

targeting the proton pump of ATP synthase [78].

PZA with DRQ TMC207 hasten activity [80].

**Diarylquinoline compounds**

*Diarylquinoline TMC207*

**Purine Analogs**

*Benzylpurines*

**40**

known [83].

Various 1,2,4-triazoles have been estimated against *Mtb* H37Rv. Compound (**1**)

A series of imidazo(4,5-c)pyridines, one compound (**2**) for common formula (R1, R2 unrevealed)-inhibited *Mtb*H37Rv and other strains with MICs range 0.256– 2.56 μg/ml. Imidazo(4,5-c)pyridines were initially prepared as anti-mitotic agents but in the present work, fewer cytotoxic agents were chosen and found to have anti-

Diarylquinolines (DARQs) is structurally unlike both FQs and other quinolines derivatives. The DARQ R207910 is a new class of anti-TB drugs. It has specificity towards mycobacteria as well as atypical species, important in humans such as MAC, *M. kansai,* and the fast-growing *M. fortium* and *M. abscessus* [77]. The anti-TB specific spectrum differs from that of INH, which has very poor activity against MAC. It will be extremely targeted to the treatment of TB infections, mainly

Diarylquinoline (DRQ) TMC207 is an exceptionally promising class of anti-TB drugs. About, 20 compounds of the DRQ series have been exhibited a MIC value below 0.5 μg/ml against *Mtb* H37Rv [78]. The most active compound of this class is TMC207 against *Mtb*. The mechanism of action of DRQ TMC207 is different from those of other anti-TB drugs involving a low probability of cross-resistance with accessible anti-TB drugs. The DRQ TMC207 is capable to inhibit bacterial growth against MDR-TB isolates and appears to act by inhibiting the ATP synthase [79], most important to ATP depletion and pH imbalance. Substitutions of RIF, INH, or

The 9-Benzylpurines, with a variety of substituents on 2, 6, and/or 8 positions, have high inhibitory activities against *Mtb*. One compound, carrying trans-styryl or aryl substituents at 6 positions and generally chlorine in 2 positions tends to increase the *in vitro* activity and has MIC of 0.78 mg/mL [81]. The anti-TB activity of 6 arylpurines [82] and 9-sulphonylated or sulphenylated-6-mercaptopurines are also

The 9-benzylpurines, 2-chloro-4(2-furanyl)-9-benzylpurine was potently inhibited *Mtb* H37Rv *in-vitro* with a MIC value of 0.78 μg/ml with low cytotoxicity towards VERO cells (IC50 value-8.1 μg/ml) selectivity index (MIC/IC50) of 10.4 [4].

gave 61% inhibition at 6.25 μg/ml. Other triazole analogs were inactive [2–4].

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

Naturally occurring (5*R*)-thiolactomycin (TLM) exhibits potent *in vivo* activity against many pathogenic bacteria, and *Mtb* [84]. TLM inhibited bacterial and plant type II fatty acid synthases (FAS-II) but not inhibited mammalian or yeast type I fatty acid synthases (FAS-I) [85]. In *E. coli*, it inhibited both β-ketoacyl-ACP synthase I to III and acetyl coenzyme A (CoA): ACP transacylase activities [86, 87]. The TLM was the first example of naturally occurring thiolactone to displayed antibiotic action. The TLM analogs have improved activity against whole cells of pathogenic *Mtb* strains [88]. The TLM analogs act by the inhibition of the mycolate synthase, an enzyme involves in the biosynthesis of the *Mtb* cell wall.

This has led to the hope that inhibitors of the TLM target enzyme, FAS-II, are potentially important in the treatment of malaria [89], trypanosomiasis, or sleeping sickness [90], and a range of bacterial indications including TB. It also blocks longchain mycolate synthesis in a dose-dependent mode [91]. The TLM is active *in vitro* against an extensive range of strains of *Mtb*, including INH- resistant, although at somewhat high concentrations. For example, complete inhibition of growth on solid media of the strain *Mtb* Erdman is seen at 25 μg/ml. The TLM itself as an anti-TB agent [92] and racemic mixtures, e.g. compounds (**A**) and (**B**), which are accounted to have superior activity than the parent in inhibiting *Mtb* H37Rv *in-vitro*.

#### **Mefloquine Analogues**

The antimalarial agent mefloquine and its analogs have activity against a range of bacteria including *Mtb* [93]. A series of quinolinemethanol analogs, two compounds, WR-3016, and WR-3017, exhibited potent inhibitory effects in vitro in the *M. avium* complex-1 (MAC) assay with MIC50 values of 1 and 2 μg/ml respectively, compared to 16 μg/ml for mefloquine. Other mefloquine analogs, two enantiomers of mefloquine and might be valuable to test some representative 4-aminoquinoline antimalarials such as chloroquine [94]. Another compound desbutylhalofantrine (**3**) is in progress for its antimalarial activities with an advantage over the parent drug halofantrine of lesser cardiotoxicity.

#### *Deazapteridines*

Some 2,4-diamino-5-deazapteridine derivatives, SRI-20094 has potent inhibition of MM6 cells infected with MAC strain NJ3440 with a MIC value 0.13 μg/ml. SRI-20094 inhibits the dihydrofolate reductase (DHFR) of the MAC, with an IC50 value 1.0 nM as compared to 4100, 1.4 and 1.0, nM for the trimethoprim,

piritrexim, and trimetrexate,. It confirmed limited inhibition for human DHFR having an IC50 value 7300 nM. SRI-20094 is a value for the *M. avium* infection and in particular for HIV co-infected persons. Other close analogs were highly active against *Mtb* with MICs of 0.1 mg/l [95].

**Tryptanthrin derivatives**

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

to both clofazimine and RIF drug [14, 15].

**Phenazine B4157**

**Toluidine Derivatives**

**43**

Tryptanthrin is an indoloquinazolinone containing alkaloid and evaluated against different strains of *Mtb* including the drug-sensitive *Mtb* H37Rv strain. The MIC value of tryptanthrin was 1.0 μg/ml compared to the MIC value of INH was 0.03 μg/ml. When evaluated against a section of MDR-TB strains, even as

tryptanthrin sustain its effectiveness (MIC = 0.5-1 μg/ml), INH had declined activity with MIC value 4-16 μg/ml. Many derivatives have been tested for their potential in TB treatment like PA-505 having powerful *in vitro* activity towards *Mtb* H37Rv-MIC 0.015 μg/ml and had only modest actions in reducing *Mtb* in the spleen

**Clofazimine or Tetramethylpiperidino (TMP) Phenazines Analogues** The tetramethyl piperidine substituted phenazines B4169 and B4128 (TMP phenazines) have possessed significantly activity against *Mtb*, including MDR clinical strains than clofazimines [103]. Recently, new conjugates of phenazine with phthalimido and naphthalimido moieties (**12**) have anti-TB activity [33]. Some phenazine hybrids have shown potential inhibition of *Mtb* ATCC 27294 as well as their clinical isolates (both sensitive and resistant). There is a potential to design new phenazine hybrids for the research and development of new anti-TB agents [14]. The anti-TB effects of tetramethyl piperidinophenazine derivatives are closely related to the clofazimine. The intra- and extracellular effects of these drugs were compared to clofazimine and RIF against *Mtb* H37Rv. The B4169 has effectively inhibited the bacterium with a MIC value of 0.015 μg/ml; the equivalent value for clofazimine was 0.06 μg/ml. These compounds were more active than clofazimine against a series of *Mtb* isolates plus MDR-TB strains. Besides, some derivatives, B4128, exhibited significant intracellular activity (60% inhibition of growth) at 0.001 μg/ml against *Mtb* infected monocyte-derived macrophages and were better

The B4157 is a phenazinamine derivative, closely related to clofazimine, has a potential action for TB. *In vitro*, clofazimine and B4157 were screened against various *Mtb* strains, most of resistance strains, and all were vulnerable to B4157 including which were resistance to clofazimine. The MICs value of B4157 and clofazimine at which 90% of strains inhibited were 0.12 and 1.0 μg/ml. However, C57BL against *Mtb* at 20 mg/kg, clofazimine was slightly better to B4157 [4, 15].

Some analogs of toluidines have attractive *in vitro* activity against *Mtb* 103471, the best compound (**14**), having MICs values 4 μg/ml-cf MICs of INH, 0.25 μg/ml,

of infected mice when given orally at 50 mg/kg/day for ten days [102].

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

### *1,2,4-Benzothiadiazines*

The 1,2,4-benzothiadiazine dioxides have a close relation to sulfonamide and could be considered as cyclic sulfonamides. These compounds exhibited antimicrobial activity [96]. The 1,2,4-benzothiadiazines were explored by incorporating other heterocyclic rings like pyridine and pyrazine moieties (**4** and **5**) and these compounds were exhibited interesting anti-TB activity [97].

#### *Other Molecules*

Several other molecules like pyrroles (**6)** [98], quinoxaline-1,4-dioxides (**7**) [99], and alkylsulfinyl amides (**8**) [100] have been tested for their anti-TB activity. In the analysis of the constant MDR-TB problem, new drugs should concentrate on different targets, including the reduction of TB therapy [101], with negligible toxicity and thus structures based on this lead could provide a novel class of anti-TB drugs.

#### **Benzoxazine derivatives**

Some 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(*3H*)-ones (**9**) and 6 chloro-3-phenyl-2H-1,3-benzoxazine-2,4(*3H*)-dithiones (**10**) have potent anti-TB activity against *Mtb* (MIC values 0.5 mcmol/l), *M. avium* (16 and 16 μmol/l), *M. kansasii* (2 and 2 μmol/l), and *M. kansaii* (1 and 0.5 μmol/l), compared with MIC values of 4, 8, 500 and 500 μmol/l for INH after 14 days [4].

#### **Diterpenoids**

Marine products gorgonian coral *Pseudopterogorgia elisabethae* from the West Indian have the anti-TB activity of two active diterpenoid alkaloidal compounds, secopseudopteroxazole and pseudo-pteroxazole [4, 71]. The pseudopteroxazole against *Mtb* H37Rv was claimed to be a powerful inhibitor giving 97% growth inhibition at 12.5 μg/ml even as seco-pseudopteroxazole was rather less active. Some of these derivatives are significantly more active than the marine diterpenoids (11) with the MIC value of *Mtb* H37Rv = 0.46 μg/ml.

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Tryptanthrin derivatives**

piritrexim, and trimetrexate,. It confirmed limited inhibition for human DHFR having an IC50 value 7300 nM. SRI-20094 is a value for the *M. avium* infection and in particular for HIV co-infected persons. Other close analogs were highly active

The 1,2,4-benzothiadiazine dioxides have a close relation to sulfonamide and could be considered as cyclic sulfonamides. These compounds exhibited antimicrobial activity [96]. The 1,2,4-benzothiadiazines were explored by incorporating other heterocyclic rings like pyridine and pyrazine moieties (**4** and **5**) and these com-

Several other molecules like pyrroles (**6)** [98], quinoxaline-1,4-dioxides (**7**) [99], and alkylsulfinyl amides (**8**) [100] have been tested for their anti-TB activity. In the analysis of the constant MDR-TB problem, new drugs should concentrate on different targets, including the reduction of TB therapy [101], with negligible toxicity and thus structures based on this lead could provide a novel class of anti-TB drugs.

Some 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(*3H*)-ones (**9**) and 6 chloro-3-phenyl-2H-1,3-benzoxazine-2,4(*3H*)-dithiones (**10**) have potent anti-TB activity against *Mtb* (MIC values 0.5 mcmol/l), *M. avium* (16 and 16 μmol/l), *M. kansasii* (2 and 2 μmol/l), and *M. kansaii* (1 and 0.5 μmol/l), compared with MIC

Marine products gorgonian coral *Pseudopterogorgia elisabethae* from the West Indian have the anti-TB activity of two active diterpenoid alkaloidal compounds, secopseudopteroxazole and pseudo-pteroxazole [4, 71]. The pseudopteroxazole against *Mtb* H37Rv was claimed to be a powerful inhibitor giving 97% growth inhibition at 12.5 μg/ml even as seco-pseudopteroxazole was rather less active. Some of these derivatives are significantly more active than the marine diterpenoids (11)

against *Mtb* with MICs of 0.1 mg/l [95].

pounds were exhibited interesting anti-TB activity [97].

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

values of 4, 8, 500 and 500 μmol/l for INH after 14 days [4].

with the MIC value of *Mtb* H37Rv = 0.46 μg/ml.

*1,2,4-Benzothiadiazines*

*Other Molecules*

**Diterpenoids**

**42**

**Benzoxazine derivatives**

Tryptanthrin is an indoloquinazolinone containing alkaloid and evaluated against different strains of *Mtb* including the drug-sensitive *Mtb* H37Rv strain. The MIC value of tryptanthrin was 1.0 μg/ml compared to the MIC value of INH was 0.03 μg/ml. When evaluated against a section of MDR-TB strains, even as tryptanthrin sustain its effectiveness (MIC = 0.5-1 μg/ml), INH had declined activity with MIC value 4-16 μg/ml. Many derivatives have been tested for their potential in TB treatment like PA-505 having powerful *in vitro* activity towards *Mtb* H37Rv-MIC 0.015 μg/ml and had only modest actions in reducing *Mtb* in the spleen of infected mice when given orally at 50 mg/kg/day for ten days [102].

#### **Clofazimine or Tetramethylpiperidino (TMP) Phenazines Analogues**

The tetramethyl piperidine substituted phenazines B4169 and B4128 (TMP phenazines) have possessed significantly activity against *Mtb*, including MDR clinical strains than clofazimines [103]. Recently, new conjugates of phenazine with phthalimido and naphthalimido moieties (**12**) have anti-TB activity [33]. Some phenazine hybrids have shown potential inhibition of *Mtb* ATCC 27294 as well as their clinical isolates (both sensitive and resistant). There is a potential to design new phenazine hybrids for the research and development of new anti-TB agents [14]. The anti-TB effects of tetramethyl piperidinophenazine derivatives are closely related to the clofazimine. The intra- and extracellular effects of these drugs were compared to clofazimine and RIF against *Mtb* H37Rv. The B4169 has effectively inhibited the bacterium with a MIC value of 0.015 μg/ml; the equivalent value for clofazimine was 0.06 μg/ml. These compounds were more active than clofazimine against a series of *Mtb* isolates plus MDR-TB strains. Besides, some derivatives, B4128, exhibited significant intracellular activity (60% inhibition of growth) at 0.001 μg/ml against *Mtb* infected monocyte-derived macrophages and were better to both clofazimine and RIF drug [14, 15].

#### **Phenazine B4157**

The B4157 is a phenazinamine derivative, closely related to clofazimine, has a potential action for TB. *In vitro*, clofazimine and B4157 were screened against various *Mtb* strains, most of resistance strains, and all were vulnerable to B4157 including which were resistance to clofazimine. The MICs value of B4157 and clofazimine at which 90% of strains inhibited were 0.12 and 1.0 μg/ml. However, C57BL against *Mtb* at 20 mg/kg, clofazimine was slightly better to B4157 [4, 15].

#### **Toluidine Derivatives**

Some analogs of toluidines have attractive *in vitro* activity against *Mtb* 103471, the best compound (**14**), having MICs values 4 μg/ml-cf MICs of INH, 0.25 μg/ml, and SM, 0.5 μg/ml. However, these amines will undergo rapid metabolic degradation, possibly toxic metabolites [4, 15].

**Poloxamer 315 (CRL-1072)**

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

SM, and RIF [114].

**Niclosamide**

**Mikasome**

extent from the intestine [115].

conventional therapies [4, 14]. **Fulleropyrrolidines**

**Pyrrole LL- 3858**

**Dipiperidine SQ-609**

shortening of the treatment time.

**ATP Synthase inhibitor FAS20013**

**Pleuromutilins**

**45**

Poloxamer 315 is a methyl oxirane surfactant polymer that shows to disrupt the cell membranes of microorganisms or their intracellular components. The purified polymer is effective against *Mtb* and *M. avium*. *In vitro* effect against *Mtb* showed MIC values 3.1–6.2 μg/ml even as, in a macrophage assay, these go down to 0.92 to 1.25 μg/ml. This compound was effective against strains of *Mtb* resistant to INH,

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

The anthelmintic drug niclosamide was found to have anti-TB activity *in vitro* (MIC 0.5-1 μg/ml) against *Mtb* H37Ra. However, niclosamide is useful for the treatment of human tapeworm infections; it is not absorbed to any significant

The liposome-encapsulated drug for the anti-TB activity, Mikasome, is useful against *M. avium* infections *in vitro* and *in vivo*. In animals, Mikasome formed 7-fold higher peak plasma levels compared to free drug amikacin (i.v.). The AUC was 150 fold higher with the liposomal substance and a single dose of liposomal amikacin formed therapeutic levels of antibiotics for more than 72 hr. The pilot Phase II studies showed that MiKasome was capable to resolve *Mtb* infections who had failed

A series of fullerene analogs, compound (**2.158**) exhibited anti-TB activity. It inhibited the growth of a human clinical isolate, *Mtb* H6/99, MIC value of 5 μg/ml, and *Mtb* H37Rv MIC value of 50 μg/ml. Some fullerene derivatives have also exhibited *in-vitro* activity against the HIV protease contributing to the tantalizing

Some pyrroles analogs were effective *in-vitro* against the standard and drugsensitive *Mtb* strains [116]. Compounds LL-3858 was exhibited a higher bactericidal

Dipiperidine SQ-609 is structurally dissimilar to the existing anti-TB drug. It destroyed *Mtb* by interfering with cell wall biosynthesis. The antimicrobial effect

The pleuromutilins is a novel natural antibiotic. They interfere with protein synthesis by binding to the 23S rRNA and consequently inhibiting the formation of a peptide bond [118]. The cross-resistance might happen between pleromutilins and oxazolidinones [119]. Pleuromutilins have been revealed to in-vitro inhibition of the *Mtb* growth. The pleuromutilin compound is active against MDR-TB and permitted

The FAS20013 belongs to the β-sulphonylcarboxamide analogs. FAS20013 destroys more organisms in a 4-hour exposure than INH or RIF can throughout a

option of combined actions towards both AIDS and TB [2–4].

effect than INH when given as monotherapy to infected mice.

has been established *in vivo* in mice models [117–119].

#### **Saccharides**

The arabinose disaccharide SR-9581 is *in vitro* effective against *Mtb*, with a MIC value 4 μg/ml. It reduced the viability of *Mtb* 76.1%, 97.8%, and 99.9% at 8, 16, and 32 μg/ml in 3 days. Another saccharide, an arabinofuranoside oligosaccharide (**14**), substrate for mycobacterial arabinosyltransferases, both compounds can disrupt biosynthesis of *Mtb* cell wall [104, 105].

#### **Oxazolidinones (Linezolid)**

The Oxazolidinones are a class of broad-spectrum antibiotic compounds. They inhibit protein synthesis through binding to the 50S subunit of ribosomes. Oxazolidinones had considerable activities against *Mtb in-vitro* in mice [106]. Oxazolidinones are less promising due to their toxicities and high-cost value [107, 108].

#### *Oxazolidinones PNU 100480 and AZD 2563*

They have bacteriostatic activity against various human pathogens together with drug-resistant microorganisms [109, 110]. The oxazolidinones have activity against *Mtb* and linezolid (U-100766) inhibiting MDR isolates *in vitro* at 2 μg/ml [111]. Oxazolidinones having a thiomorpholine group in place of the morpholine group present in linezolid has mainly active against *Mtb* with MICs value 0.125 μg/ml [112]. PNU-100480 was also tested in a murine model against ten strains of *Mtb* in comparison to linezolid and INH. PNU-100480 was found equivalent to INH and more active than linezolid [106].

#### **Calanolides**

Calanolide A is a naturally pyranocoumarin that has double action against TB and HIV infections. This compound is an inhibitor of the HIV-1 reverse transcriptase enzyme. It also exhibits good in vitro effects towards *Mtb*. In a beginning test of its activity, calanolide A was analogous to the positive control INH and staying effective against RIF and SM resistant TB strains. Calanolide A decreasing the dependency upon acquiring the material from limited natural resources [4, 27] and some compounds, e.g. (**15**), have patented for their anti-TB activities. Calanolide B, which distinct calanolide A, is existing in considerable quantities from renewable natural sources, e.g. from Calophyllum seed oil, [113] has a similar range of activity to calanolide A against *Mtb* and may be an additional costeffective treatment.

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Poloxamer 315 (CRL-1072)**

and SM, 0.5 μg/ml. However, these amines will undergo rapid metabolic degrada-

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

The arabinose disaccharide SR-9581 is *in vitro* effective against *Mtb*, with a MIC value 4 μg/ml. It reduced the viability of *Mtb* 76.1%, 97.8%, and 99.9% at 8, 16, and 32 μg/ml in 3 days. Another saccharide, an arabinofuranoside oligosaccharide (**14**), substrate for mycobacterial arabinosyltransferases, both compounds can disrupt

The Oxazolidinones are a class of broad-spectrum antibiotic compounds. They

They have bacteriostatic activity against various human pathogens together with drug-resistant microorganisms [109, 110]. The oxazolidinones have activity against *Mtb* and linezolid (U-100766) inhibiting MDR isolates *in vitro* at 2 μg/ml [111]. Oxazolidinones having a thiomorpholine group in place of the morpholine group present in linezolid has mainly active against *Mtb* with MICs value 0.125 μg/ml [112]. PNU-100480 was also tested in a murine model against ten strains of *Mtb* in comparison to linezolid and INH. PNU-100480 was found equivalent to INH and

Calanolide A is a naturally pyranocoumarin that has double action against TB and HIV infections. This compound is an inhibitor of the HIV-1 reverse transcriptase enzyme. It also exhibits good in vitro effects towards *Mtb*. In a beginning test of its activity, calanolide A was analogous to the positive control INH and staying effective against RIF and SM resistant TB strains. Calanolide A decreasing the dependency upon acquiring the material from limited natural resources [4, 27]

and some compounds, e.g. (**15**), have patented for their anti-TB activities. Calanolide B, which distinct calanolide A, is existing in considerable quantities from renewable natural sources, e.g. from Calophyllum seed oil, [113] has a similar range of activity to calanolide A against *Mtb* and may be an additional cost-

inhibit protein synthesis through binding to the 50S subunit of ribosomes. Oxazolidinones had considerable activities against *Mtb in-vitro* in mice [106]. Oxazolidinones are less promising due to their toxicities and high-cost value

tion, possibly toxic metabolites [4, 15].

biosynthesis of *Mtb* cell wall [104, 105].

**Oxazolidinones (Linezolid)**

more active than linezolid [106].

**Calanolides**

effective treatment.

**44**

*Oxazolidinones PNU 100480 and AZD 2563*

[107, 108].

**Saccharides**

Poloxamer 315 is a methyl oxirane surfactant polymer that shows to disrupt the cell membranes of microorganisms or their intracellular components. The purified polymer is effective against *Mtb* and *M. avium*. *In vitro* effect against *Mtb* showed MIC values 3.1–6.2 μg/ml even as, in a macrophage assay, these go down to 0.92 to 1.25 μg/ml. This compound was effective against strains of *Mtb* resistant to INH, SM, and RIF [114].

#### **Niclosamide**

The anthelmintic drug niclosamide was found to have anti-TB activity *in vitro* (MIC 0.5-1 μg/ml) against *Mtb* H37Ra. However, niclosamide is useful for the treatment of human tapeworm infections; it is not absorbed to any significant extent from the intestine [115].

#### **Mikasome**

The liposome-encapsulated drug for the anti-TB activity, Mikasome, is useful against *M. avium* infections *in vitro* and *in vivo*. In animals, Mikasome formed 7-fold higher peak plasma levels compared to free drug amikacin (i.v.). The AUC was 150 fold higher with the liposomal substance and a single dose of liposomal amikacin formed therapeutic levels of antibiotics for more than 72 hr. The pilot Phase II studies showed that MiKasome was capable to resolve *Mtb* infections who had failed conventional therapies [4, 14].

#### **Fulleropyrrolidines**

A series of fullerene analogs, compound (**2.158**) exhibited anti-TB activity. It inhibited the growth of a human clinical isolate, *Mtb* H6/99, MIC value of 5 μg/ml, and *Mtb* H37Rv MIC value of 50 μg/ml. Some fullerene derivatives have also exhibited *in-vitro* activity against the HIV protease contributing to the tantalizing option of combined actions towards both AIDS and TB [2–4].

#### **Pyrrole LL- 3858**

Some pyrroles analogs were effective *in-vitro* against the standard and drugsensitive *Mtb* strains [116]. Compounds LL-3858 was exhibited a higher bactericidal effect than INH when given as monotherapy to infected mice.

#### **Dipiperidine SQ-609**

Dipiperidine SQ-609 is structurally dissimilar to the existing anti-TB drug. It destroyed *Mtb* by interfering with cell wall biosynthesis. The antimicrobial effect has been established *in vivo* in mice models [117–119].

#### **Pleuromutilins**

The pleuromutilins is a novel natural antibiotic. They interfere with protein synthesis by binding to the 23S rRNA and consequently inhibiting the formation of a peptide bond [118]. The cross-resistance might happen between pleromutilins and oxazolidinones [119]. Pleuromutilins have been revealed to in-vitro inhibition of the *Mtb* growth. The pleuromutilin compound is active against MDR-TB and permitted shortening of the treatment time.

#### **ATP Synthase inhibitor FAS20013**

The FAS20013 belongs to the β-sulphonylcarboxamide analogs. FAS20013 destroys more organisms in a 4-hour exposure than INH or RIF can throughout a 12- to 14-day exposure. This compound is especially effective in killing MDR-TB strains that are resistant to currently used multiple drugs. The greater effect of FAS20013 compared to current anti-TB drugs in terms of its ability to sterilize TB injuries and kill latent TB strains. The FAS20013 has its efficiency in mice with no serious adverse effects and it is up to 100% bioavailable when orally used. The compound is acted by inhibition of ATP synthase [120].

## **Diamine SQ-109**

Diamine SQ-109 was developed as a second-generation drug from the first-line drug ethambutol (EMB). When examined in a low-dose infection model of TB in mice, SQ-109 at 1 mg/kg was as efficient as EMB at 100 mg/kg. However, SQ-109 did not prove improved efficacy at higher doses (10 mg/kg; 25 mg/kg) and was less efficient than INH [121]. The SQ-109 is effictive against MDR-TB, together with those that are EMB-resistant.

#### **Nitrofuranylamides**

The *Mtb* is relatively vulnerable to Nitro-containing compounds [122]. Nitrofuranylamide (**16**) was accepted in testing for UDP-Gal mutase inhibition. A prolonged set of nitrofuranylamides was tested for anti-microbial activity. This led to the recognition of several nitrofuranylamides with activity effective against *Mtb* [123].

### **6. Conclusion**

Tuberculosis (TB) is a chronic infectious disease caused by *M. tuberculosis*. Anti-TB drugs developed since the 1940s and their discovery resistance also developed against them. Acquired and primary drug resistances are the common pathways for the development of anti-TB drug resistance. Anti-TB drugs mainly act on protein synthesis, folic acid synthesis, mycolic acid synthesis, DNA synthesis, and ATP synthase. These anti-drugs cause bacteriostatic and/or bactericidal effects on the mycobacterium. The major resistance mechanism is the mutation of the target gene responsible for the action of anti-TB drugs. Anti-TB drug resistance produces a destructive effect on public health. Therefore, the advance study should be conducted in the areas of finding new targets for the development of novel anti-TB drugs.

**Author details**

**47**

Saad Alghamdi<sup>1</sup> and Mohammad Asif2

Research, Dehradun, Uttarakhand, India

provided the original work is properly cited.

Umm Al-Qura University, Makkah, Saudi Arabia

\*Address all correspondence to: aasif321@gmail.com

\*

2 Department of Pharmaceutical Chemistry, Himalayan Institute of Pharmacy

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Laboratory Medicine Department, Faculty of Applied Medical Sciences,

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*
