Review article
Recent advances in drug discovery against Mycobacterium tuberculosis: Metal-based complexes

https://doi.org/10.1016/j.ejmech.2021.113166Get rights and content

Highlights

  • Evaluation of the anti-Mycobacterium tuberculosis activity of metal-based complexes in last decade.

  • The most actives ligands and its derivatives with different metals.

  • Correlation of the derivatives in relation to MIC values and its metals.

  • Perspectives to metal-based complexes analogues against Mycobacterium tuberculosis.

Abstract

Metal-based drugs are privileged motifs that act as primary pharmacophores in bioactive compounds for various diseases, including tuberculosis (TB). This potentially life-threatening and extremely contagious infectious disease is caused by Mycobacterium tuberculosis (Mtb). In 2018, TB infected about 10 million people and caused 1.2 million deaths worldwide. A large number of ligands are promising scaffolds in drug design, including heterocyclic, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates and miscellaneous. Moreover, several metal-based complexes have been studied for the treatment of numerous illnesses, including infectious diseases. To contribute to drug design, we identified the metal-based organometallic complexes against Mtb. Thus, in this review article, we analysed the recent contributions of metal-based scaffolds for design of new anti-Mtb drugs in the last decade (2011–2020). Besides, metal-based approaches will be presented in order to find out new antitubercular agents.

Introduction

Tuberculosis, the leading infectious cause of death worldwide, is an infectious disease transmitted when a person with an active lung infection sprays mycobacteria-containing droplets into the air through coughing, sneezing or talking [1]. Since 1993, World Health Organization (WHO) has declared TB as a global health emergency. In recent years, deaths caused by TB surpass those from human immunodeficiency virus (HIV) and malaria combined [2,3]. During the last two centuries, it has been estimated that one billion people died from TB [3].

The challenge to mitigate TB increases considering the emergence of resistance, being a current obstacle to provide prevention and effective care to all those vulnerable people. Nowadays, the arrival of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains has posed considerable treatment challenges. Some estimatives pointed out that the number of MDR-TB-infected patients achieved about 484,000 with an estimated number of deaths around 284,000. Multidrug-resistant strains (MDR-TB) are defined in those conditions in which there is resistance to at least isoniazid and rifampin, while XDR-TB exhibits additional resistance to second-line injectable drugs and fluoroquinolone, demanding long-term treatments exposing the patients to more adverse effects [[4], [5], [6], [7], [8]]. The factors associated to the emergence of multidrug-resistant TB (MDR-TB) are multiple. Some causes that induce Mtb-resistance can be related to unappropriated treatments due to the lack of therapy adherence, poor drug supply management in developing countries, low quality of drugs, airborne transmission of mycobacteria in public and crowded places and co-infections such as HIV in which treatment using multiple drugs can favour drug-drug interactions, reducing the efficacy of antitubercular drugs [[4], [5], [6], [7], [8]]. Low economic, educational and social conditions associated with stigma make this scenario catastrophic, imposing barriers to the elimination of the disease proposed until 2035 [[9], [10], [11]].

More than 50 years ago, Rosenberg’s research team reported the antitumor activity of cis-diaminedichloroplatinum(II) [12], a metal-based complex. Ever since, metal-based complexes have attracted considerable attention due to their wide range of pharmacological properties, such as antibacterial [[13], [14], [15], [16], [17], [18]], antiparasitic [[19], [20], [21]], anticonvulsant [[22], [23], [24]], anti-Alzheimer’s disease [[25], [26], [27], [28]], anti-diabetic [[29], [30], [31], [32]], anti-inflammatory [[33], [34], [35]], anti-proliferative [[36], [37], [38], [39], [40], [41], [42]], and antitubercular activity [[43], [44], [45], [46]]. Metals are essential elements that are paramount to homeostasis in humans [47]. In the drug discovery field, transition metal complexes offer new opportunities that are not found for small organic molecules.

The rich variety of coordination geometry and oxidation states of transition metal ions allow the design of many distinct complexes, containing either labile or inert coordinate bonds. Kinetic and thermodynamic properties of metal complexes for therapeutic purposes can be modulated by the careful election of the oxidation state and set of ligands [[48], [49], [50]]. The choice of suitable ligands allows controlling important physico-chemical parameters, such as lipophilicity/hydrophilicity, reactivity and/or substitutional inertness, kinetics of demetallation, and hydrolytic stability [50]. In this context, metals can act as inert scaffolds capable of bringing together a set of appropriate ligands in a unique, precise, and predictable three-dimensional shape. These metal compounds may possess stereo-electronic complementarity with defined pharmacological targets [51]. On the other hand, direct covalent binding of a labile metal complex to cellular biomolecules may induce biological effects. This is the case of the anti-tumour agent cisplatin (cis-[PtCl2(NH3)2]), the most well-known metal-based drug. Cisplatin undergoes hydrolysis and then interacts covalently with DNA and/or other specific biological targets, inducing apoptosis in tumour cells [[52], [53], [54], [55]].

Therefore, the search for new drugs is one of the pillars recommended by the WHO in order to mitigate the disease in the coming years. Among the drug design approaches, those using metal complexes have shown to be promising. The metal-based compounds have received a lot of attention in the last years. At the beginning of the century, Bottari and collaborators (2001) showed the potent activity of the bis (benzoyl-hydrazonate) 2,6-diacetylpyridine nickel(II)-based complex against Mtb, with a minimal inhibitory concentration (MIC) of 0.025 μg/mL−1. This MIC value is ten times more active than rifampicin, and its power is equal to isoniazid. The authors also demonstrated that the presence of nickel(II) is fundamental, as it enhances lipophilicity. Ligands without the presence of nickel were completely inactive against Mtb [56]. Three years later, Oliveira and co-workers (2004) developed an inorganic iron-based complex [FeII(CN)5(INH)]3 that inhibited wild-type and isoniazid-resistant mutant 2-trans-enoyl-ACP (CoA) reductase from Mtb, and presented an excellent MIC value of 0.2 mg/mL−1 [57]. Ruthenium-based complexes were identified by Pavan and collaborators [58,59] as having promising activity against Mtb. These Ruthenium-based complexes exhibited activity that was up to 150 times higher against MTB than free ligands, besides the in vitro results being promising when compared to first-line drugs. In addition, these Ruthenium-based compounds were found not to be toxic (Ames test), genotoxic (mutagenicity essay), or cytotoxic. Currently, nanotechnology is improving the absorption, biodistribution and stability of these complexes.

Thus, inorganic medicinal chemistry has greatly advanced in the last few decades [[60], [61], [62], [63], [64], [65]]. This review article provides critical analysis and reports the metal-based complexes that are useful to treat TB. In order to report the most recent compounds, we included only molecules described from 2011 to 2020 in the databases PubMed, Scopus, and the Web of Science (Fig. 1). Perspectives which contribute to drug design of new compounds are presented and discussed.

Section snippets

New anti-Mtb metal-based compounds

The search of new metal complexes for medicinal purposes represents a very active research field [[66], [67], [68]]. Examples of active complexes with biological effects include those containing platinum (Pt-), gold (Au-), silver (Ag-), iron (Fe-), palladium (Pd-), gadolinium (Gd-), samarium (Sm-), technetium (Tc-), arsenic (As-), antimony (Sb-), and bismuth (Bi-) [19]. Although much of the research in this field has been devoted to complexes for anticancer chemotherapy and diagnosis, there has

Perspectives

A final analysis about all metal-based complexes presented here have exhibited their importance to medicinal chemistry. Several scaffolds are emerging as promising agents in drug discovery programs, including heterocyclic, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates and miscellaneous. Metal complexes have been researched in the last decade for the treatment of various illnesses, including infectious diseases. Metal-based organometallic

Final Remarks

For the medicinal chemistry field, the potential of metal-based complexes needs further investigation, especially for infectious diseases, such as TB. Researches shown in this article demonstrate the potential of metal complexes to act as warheads that lead to covalent bonding with targets, specifically in the anti-Mtb and anti-tumour areas. Biological activity, pharmacodynamic propriety, and pharmacokinetic parameters are modified by the inclusion of these metallic atoms. This review article

Author’s contribution

C·B.S. designed the review, analysed the data and papers, performed the analyses, and wrote the manuscript, with input from R.L.F., J.L.S., F.R.P., A.V.G.N., and C.M.C. All authors reviewed the manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financed in part by the Coordenação de Aperfeiçoamento Pessoal de Nível Superior - Brasil (CAPES) – Finance code 001. Moreover, the authors would like to thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP - 2016/10847-9) by the research fellowships assistance. RLF is an associate researcher in the project ‘Obtaining a thiona-derived product with activity against pathogens’ funded by CNPq, Proc. PIB8926-2020, and acknowledges Professor Adriano Bof de Oliveira (

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