A Brief Overview on Recent Advances in the Development of Anti-Tubercular Compounds Containing Different Heterocyclic Ring Systems

Tuberculosis (TB), a leading cause of mortality and morbidity with more than one-third of the world population infected with latent TB and the worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health. Hence, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death to zero level. Various new drugs progress to be developed for the treatment of MDR-TB. Several new molecules in clinical development encourage the scientific community to find new drug targets and new drug leads. In this perspective we present herein an overview of the new anti-TB agents with different molecular structures. Here we have tried to provide some efforts that are being made in the development of new drug molecules as lead antiTB agents.


Introduction
Heterocyclic chemistry is the branch of chemistry dealing with synthesis, properties, and applications of heterocycles. Heterocycles form by far the largest of the classical divisions of organic chemistry and are of immense importance biologically, industrially, and indeed to the functioning of any developed human society. The majority of pharmaceuticals and biologically active agrochemicals are heterocyclic. There are countless heterocyclic additives and modifiers used in industries [1][2][3]. Heterocycles play an important role in biochemical processes. Heterocyclic systems occur in a wide variety of natural and synthetic compounds and are essential to life in various ways. The synthetic heterocyclic drugs are still more numerous and include most of the antimicrobials, hypnotics, anti-convulsants, analeptics, antihistaminics anti-thyroid drugs, also many antiseptics, fungicides, vasopressor modifiers and others. Heterocyclic rings constitute a large number of synthetic dyes and analytical reagents [3][4][5][6].
Tuberculosis, commonly known as TB, is an often severe and contagious airborne disease caused Mycobacterium tuberculosis (Mtb) and typically affects the lungs but can affect the other parts of the body called extrapulmonary tuberculosis (TB). The Mtb is acid-fast, gram positive bacteria, grows slowly under aerobic conditions. Multidrug-Resistant TB (MDR-TB) is defined by resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, isoniazid and rifampin. Extensively drug resistance TB (XDR-TB) is caused by Mtb resistant to isoniazid, rifampin, at least one fluoroquinolone, and one of the injectable anti-TB drugs such as amikacin, kanamycin, or capreomycin. Minimum Inhibitory Concentration (MIC) is the concentration of antibacterial that will inhibit the growth of bacteria. DOTs (Directly Observed Treatment, Shortcourse) is a strategy that framework for the TB control programme [7][8][9][10].
TB is one of humanity's oldest and most resilient plagues, despite the availability of four drug regimen to treat the disease [11]. The current first line anti-TB regimens require a minimum 6 months of DOTs therapy. Adherence to the long and complicated treatment course is challenging and is a major obstacle to the effective use of existing drugs [12]. As a result of treatment failure and poor observance, epidemic with MDR-TB or XDR-TB is being more common [13]. In 2011, the number of MDR-TB infections was estimated at 60,000 cases (19 % of the global infected population) [4]. Suggested regimens for MDR-TB therapy require at least 20 months of treatment with drugs that are toxic, poorly tolerated, and limited efficacy of cure rate. According to World Health Organization (WHO) global TB report 2012, there were almost 9 million new cases in 2011 and 1.4 million TB deaths. Besides, the emergence of drug-resistance is becoming a major threat to global TB care and control. Around 310,000 MDR-TB cases occurred among notified TB patients in 2011 [14]. The increasing emergence of DR-TB and HIV infection which compromises host defense and allows latent infection to reactivate TB and posed further challenges for effective control of TB. Moreover, TB treatment is lengthy (takes 6-9 months) with significant toxicity, which creates poor patient compliance resulting in a frequent cause for selection of drug resistant and often deadly MDR-TB bacteria [15]. In 2013, 6.1 million TB cases were reported out of these, 5.7 million were newly diagnosed. Number of MDR-TB infections was estimated at 23% of reported TB patients. 1.1 million (13%) of the 9 million people who developed TB in 2013 were HIV-positive. About 60% of TB cases and deaths occur among men and 510000 women died as a result of TB, more than one third of whom were HIV-positive. There were 80000 deaths from TB among HIV negative children in the same year [16]. The emergence of highly lethal, expensive and virtually untreatable XDR-TB poses a new threat to TB control. The control of TB is complicated due to latent TB where the infected persons are asymptomatic, and serve as the reservoir for the pathogen, making control of this disease a difficult and challenging task [17]. In 2014, the WHO estimated 9 million new TB cases had occurred globally in 2013, 480000 of them being affected by MDR-TB strains [18]. The MDR-TB treatment success is only 54% (with 15% death, 8% failure/relapse and 23% default). When the drug resistance profile is beyond XDR (with increasing complexity), the outcomes are unfortunately lower: treatment success ranges from 40% to 19%, failure/relapse from 15% to 54% and death from 15% to 35% [19,20]. Every day, clinicians managing these cases face relevant challenges that include frequent occurrence of adverse events, problems in patients' adherence, lack of clinical experience, and limited availability of adequate diagnostics and second-line anti-TB drugs. The risk of acquiring further drug resistance is therefore real. WHO has launched its innovative "End TB Strategy", supporting the TB elimination strategy and the vision of a TB-free world with zero death, disease and suffering due to TB [21][22][23]. The strategy clearly supports universal access to high-quality MDR-TB diagnosis and treatment [24]. The need for new drugs and regimens is obvious [25].
Recent advances in the knowledge of molecular biology and Mtb genome sequences has enabled the essentiality of genes for the rapid target identification for the new anti-TB agents via identification of mutated genes of compound-resistant mutants [26,27]. Effective treatment of TB patients co-infected with HIV is complicated due to drug-drug interactions between anti-retrovirals (ARVs) and antituberculosis drugs and increased the risk of adverse effects. There is urgent need for more effective and tolerable anti-tuberculosis therapy for the treatment of drug-susceptible, drug-resistant disease and latent-TB infection [28]. Regimens that can be safely coadministered with antiretroviral therapy are urgently needed for the growing number of patients co-infected with both HIV and TB. These approaches include increased funding for research in antibiotic resistance and drug development for TB, development of methods for protecting the efficacy of existing drugs, and prioritization for making use of current non-TB drugs for TB treatment [29]. Among MDR-TB patients started on treatment globally in 2009, only 48% were treated successfully, largely as a result of a high frequency of patient deaths (15%) and loss to follow-up (28%), which is commonly associated with adverse drug reactions, among other factors. New drugs that would help build a better, safer, less toxic, shorter and cheaper regimen are therefore urgently needed to reduce patient suffering and mortality [30]. It has been over 40 years since a new drug for tuberculosis has been discovered [31]. Therefore, the development of innovative, effective drug combinations should also be encouraged to diversify therapeutic choices, especially those for drug resistant TB cases [29].

Designing a regimen to treat TB
The treatment regimens approved TB drugs and the dosage of anti-TB drugs recommended by the evidence-based WHO guidelines. "New" and "retreatment" cases are clearly separated, 30 days of previous anti-TB treatment being the cut-off. New TB cases (irrespective of HIV status) should be treated for the first 2 months (intensive phase) with isoniazid, rifampicin, pyrazinamide and ethambutol, followed by isoniazid and rifampicin for the remaining 4 months (continuation phase) [32]. The daily dosage is recommended (although the three times weekly dosing can be used during the continuation phase under directly observed therapy) as well as the fixed-dose combinations [33]. The aim of this review is to summarise some anti-TB compounds.
A series of quinoxaline derivatives exhibited promising anti-TB activity compound 3h of them emerged as a lead compound having IC 50 and IC 90 figures of 1.03 mM and 1.53 mM, respectively by affecting the respiration in rat liver mitochondria [48]. New lead compound 3i from Benzotriazine Di-N-Oxides series has MIC 0.31 μg/mL against H37Rv and cytotoxicity (CC 50 ) against Vero cells of 25 μg/mL. This was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity [49].

Imidazolopyridines and pyrazolotetraydropyridine
Imidazopyridines were determined to have promising anti-TB activity against replicating Mtb H37Rv, compounds 5a and 5b (

Galactopyranosyl amino alcohols
A dimeric hybrid of a galactopyranosyl amino alcohol 6 displayed potent in vitro activity with MIC 1.56 μg/mL against Mtb. However, on progression into a murine model, toxicity was observed at dosage levels (50 mg/kg per day) that offered no significant protection against Mtb infection ( Figure 6). The target of this compound is mycobacterial cell wall biosynthesis [59].  [64], and spirocromone conjugates [65] also displayed potent activity against TB.
The thiomorpholine introduction in BM 212 molecule improved its anti-TB activity. Four compounds 9a, 9b, 9c and 9d ( Figure 9) had MIC between 1 and 2 μg/mL [76,77]. Several derivatives have shown significant activities against drug-resistant TB in vitro and offer considerable protection in a rigorous mouse model of the disease [78]. Dispiropyrrolothiazoles derivative 9e showed anti-TB activity against Mtb H37Rv and INH resistant Mtb strains with MIC of 0.210 and 8.312 μM respectively [79].

Benzimidazoles
Libraries of trisubstituted benzimidazoles were created through rational drug design. A number of benzimidazoles exhibited promising

Triazolophthalazine and 3-aracylphthalide derivatives
Compound 19a, 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100-1800 times more active than Isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant Mtb strains. It does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents [141]. 3-Aracylphthalides ( Figure 19) were synthesized and were subjected to in vitro anti-TB screening against Mtb H37Ra. Among the phthalides 19b, 19c, 19d and 19e exhibited IC 50 in the range of 0.97, 0.93, 0.81 and 1.24 μg/mL respectively [142].

Tryptanthrin
Trypthanthrin is indolo-quinazolinone alkaloid ( Figure 20) and active against MDR-TB with MIC 0.5-1.0 μg/mL. In vitro toxicity and in vivo studies are needed before this structural prototype is applied as anti-TB [143].