Mini-reviewRecent progress in the drug development of coumarin derivatives as potent antituberculosis agents
Graphical abstract
The present review focus on development coumarin analogs as anti-tubercular agents. The current literature with an update of recent research and the perspectives that they hold for future research.
Introduction
Tuberculosis (TB) is an acute or chronic infectious disease caused by several species of Mycobacterium, collectively called as tubercle bacilli. TB usually attacks the lungs but can also affect the central nervous system, lymphatic system, circulatory system, genitourinary system, gastrointestinal system, bones, joints, and even the skin. It is caused by the bacterium Mycobacterium tuberculosis complex, which includes Mycobacterium tuberculosis (M. tuberculosis, [MTB]) itself, Mycobacterium microti, Mycobacterium pinnipedii Mycobacterium bovis, Mycobacterium caprae, Mycobacterium africanum, and Mycobacterium canettii [1], [2], [3]. MTB also known as the “white plague” was identified by Robert Koch in 1882 [4]. Many people become symptom-free carriers of the tubercle bacilli bacteria. Although common and deadly in the third world, tuberculosis was almost non-existent in the developed world, but has been making a recent resurgence. Certain drug-resistant strains are emerging and people with immune suppression such as acquired immune deficiency syndrome (AIDS) [5]. Person can have active or inactive TB. Active TB disease means the bacteria are active in the body and the immune system is unable to stop them from causing illness. People with active TB in their lungs can pass the bacteria on to anyone they come into close contact with. When a person with active tuberculosis coughs, sneezes or spits, people nearby may breathe in the TB bacteria and become infected. Left untreated, each person with active TB will infect on average between 10 and 15 people every year [6].
According to the World Health Organization (WHO), one third of the world's population is infected with MTB. In 2008, WHO estimated about 9.4 million incident cases of TB, 11.1 million prevalent cases of TB, 1.3 million deaths from TB among HIV-negative people and an additional 0.52 million TB deaths among HIV-positive people [7], [8]. Treatment of TB is protracted and burdensome [9] and its control is further complicated by the synergy between TB and HIV/AIDS [10], [11] and by the development of multi-drug resistant tuberculosis (MDR-TB), which can be defined as strains that have resistance to at least isoniazid (INH) and rifampicin (RIF) that are important first line drugs used in TB treatment [12]. Another serious problem in the context of MDR-TB, is the extensively drug-resistant TB (XDR-TB), which is recently emerged as a public health threat [13], [14]. Furthermore, common HIV I AIDS anti-retroviral therapies are not compatible with the current TB regimen because of shared drug toxicities and drug interactions, for example, as a consequence of RIF-induced cytochrome P450 activation [15], [16].
Therefore, people with latent tuberculosis are increasingly becoming infected with HIV and many more are developing active TB because HIV is weakening their immune system. People who are co-infected with both HIV and latent TB have an up to 800 times greater risk of developing active tuberculosis disease and becoming infectious compared with non HIV people [17]. This has spurred for novel efforts to find new anti-TB drug candidates with novel modes of action. Which includes, developing pipelines for drug discovery and development and, in particular, trying to find new regimens that can considerably shorten the duration of effective therapy which would improve patient compliance and slow down the emergence of drug-resistant strains [18], [19], [20], [21], [22], [23].
Natural, synthetic and semisynthetic heterocyclic compounds play an important role in drug discovery and chemical biology. The heterocycles are mainly of the classes of alkaloids, flavones, isoflavones, chromans, chromones, coumarins and chromenes. Synthetic compounds of these classes show different biological activity. It has been established that oxygen-containing heterocyclic compounds play an important role in designing new class of structural entities for medicinal applications [24]. Among oxygen heterocyclic compounds, coumarin (2H-chromen-2-one or 2H-1-benzopyran-2-one) (3) and its derivatives are significant because of their wide spectrum of biological activities. In recent years, a number of coumarin derivatives have been isolated from various plant sources and their extracts are being employed as traditional medicines. These are naturally occurring lactones and are also being used as perfumery and food flavoring agents. The first time, parent coumarin was first isolated from Tonka beans by Vogel in the year 1820 [25]. Coumarin ring (3) can be viewed as arising out of the fusion of pyrone ring (2) with a benzene nucleus (1). The numbering of coumarin starts from the ring oxygen i.e. oxygen receives position-1, carbonyl carbon-2 and goes round anti-clockwise along with the ring as shown below (Fig. 1.) [26].
The synthesis of coumarin and their derivatives has attracted considerable attention from organic and medicinal chemists over the decades. They are widely used as additives in food, perfumes, agrochemicals, cosmetics, pharmaceuticals [27] and in the preparations of insecticides, optical brightening agents, dispersed fluorescent and tunable laser dye [28]. Coumarin and its derivatives have varied bioactivities such as antimicrobial [29], [30], [31], [32], antidepressant [33], antioxidant [34], anti-inflammatory [35], antinociceptive [36], antitumor [37], antiasthmatic [38], antiviral [39], [40], antituberculosis [41], anti-influenza [42], anti-Alzheimer [43], [44], antihyperlipidemic [45], antipyretic [46], anti-HIV [47] activities. The discovery of coumarins having weak estrogenic activity resulted in the use of such derivatives as therapeutic agents in preventing the emergence of menopause-related diseases such as osteoporosis, increased risk of cardiovascular disease and cognitive deficiencies [48], [49]. They also show inhibitory activity on viral proteases [50], and central nervous system modulating activities [51]. Coumarins also act as intermediates for the synthesis of furocoumarins, chromenes, coumarones and 2-acylresorcinols [52].
Some of the coumarin derivatives, which are already booming in the market, to quote a few, brodifacoum (4, anticoagulant), warfarin (5, anticoagulant), difenacoum (6, anticoagulant), auraptene (7, chemopreventative agent), acenocoumarol (8, anticoagulant), ensaculin (KA-672) (9, NMDA antagonist and a 5HT1A agonist), armillarisin A (10, antibiotic), hymecromone (11, choleretic and antispasmodic), carbochromen (12, coronary disease), scopoletin (13), phenprocoumon (14, anticoagulant) and novobiocin (15, antibiotic) (Fig. 2.) [53], [54], [55].
Therefore, the synthesis of coumarin and its derivatives have received an increasing attention to synthetic organic chemists and biologists. Some reviews on involvement of coumarin nucleus as antitumor [56], [57], anti-HIV [58] and anti-Alzheimer's diseases [59], [60] are available in the literature. Some compilation reports on all activities associated with coumarin nucleus are also reported [61], [62], [63], [64], [65], [66]. But so far no review available in the literature where coumarin nucleated molecules with their application exclusively as anti-TB agents in detail. A significant amount of effort has been invested in the past decade to develop coumarin-based compounds as modulator of anti-TB, which is active on different clinically approved therapeutic targets showing excellent therapeutic potency. It is still a challenge for the pharmaceutical chemist to develop more effective and less toxic agents to treat signs and symptoms of TB disorders. By looking into the importance of this therapeutic area, it is thought to collect the data on coumarin derivatives as anti-TB agents (from 2000 to date), the indispensable anchor in medicinal chemistry. The present review reveals critical analysis of anti-TB research reports on development of different coumarin hybrids. It has been attempted to shed light and compile published reports on coumarin derivatives along with proposed of a suitable structure-activity relationship (SAR) studies. We also discussed different approaches to help the medicinal chemists in designing future generation potent yet safer coumarin-based anti-TB agents.
Section snippets
Coumarin: structural requirements for anti-TB activity
From the published data, it is evident that coumarin nucleus substituted at all positions with varied substituents has produced potent anti-TB activity except the position 1 and 2. The 3rd position of coumarin may be unsubstituted or substituents may vary from alkyl to aryl and heterocyclic groups. Among them, coumarin with fluorine, n-propyl and pyrazole substituents, demonstrated excellent anti-TB activity. Similarly, 4th position may be substituted with alkyl or bulky aryl/heteroaryl groups.
Coumarin derivatives for treatment of TB
Rezayan and co-workers reported synthesis of coumarin derivatives and their in vitro antimycobacterial activity evaluated by the broth microtiter dilution method against M. bovis and results were compared with first line anti-TB drug, ethambutol (EMB). Some of the synthesized compounds 16(a–c) found active against M. bovis. From SAR study, the size or types of substitutions (aliphatic, alicyclic, and or aromatic) at 4th position are more important than the two other positions (X and R). Also,
Coumarin-based metal complexes as anti-TB agents
Metal ions play an important role in biochemical processes. Many biochemical reactions depend on the presence of metal ions which are the part of coordination complexes [84]. It is well known that metal ions present in complexes accelerate the drug action and the efficacy of the organic therapeutic agents [85]. The pharmacological efficiencies of metal complexes having coumarin as well as other heterocyclic derivatives as ligands depend on the nature of the metal ions and the ligands [86](a),
Coumarin-based natural products as anti-TB agents
Plant-based drugs have been used worldwide in traditional medicines for the treatment of various diseases. Approximately 60% of world's populations still rely on medicinal plants for their primary healthcare. According to a survey by NCI, USA, 61% of the 877 small-molecule new chemical entities introduced as drugs worldwide during 1981–2002 were inspired by natural products [94]. Plant species still serve as a rich source of many novel biologically active compounds, as very few plant species
Conclusions and future aspects
TB remains the number one killer infectious disease affecting adults in developing countries, and there is a global emergency for this the worldwide. The situation is more complicated when one considers countries such as Africa and India where TB disproportionately affects the young. Coumarin and its derivatives are found in natural products, numerous coumarin derivatives displayed a broad spectrum of pharmaceutical and agrochemical activities, and they have also been successfully applied in
Acknowledgments
Authors acknowledge Jain University, Bangalore for the financial support. R.S.K. thanks Fundacao para a Ciencia e Tecnologia (FCT) for financial support with the project “the Postdoctoral Fellowships SFRH/BPD/75490/2010.” Also, thanks to Dr. Srinivasa Budagumpi, Assistant Professor, CNMS, Jain University, Bangalore for his useful suggestions for writing this review.
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