K Kumar Inorganic Chemistry 27.pdf
Lillia Iniguez
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Tuberculosis (TB) is a leading cause of death worldwide which is a bacillus Mycobacterium tuberculosis-based ailment and spreads when a TB patient release bacteria in air by coughing. The global TB report 2022 of the WHO demonstrates how the COVID-19 pandemic harmed tuberculosis diagnosis and unachieved target of the TB treatments worldwide1. The report analysis indicates that the undiagnosed and untreated TB patients increased in 2020 and 2021 in comparison of 2019 and currently, the TB deaths are doubled in comparison of the AIDS/HIV deaths. In future, TB will be one of the leading cause of mortality and morbidity globally by a single infectious agent, replacing COVID-192. TB also weakens the immunity of the patients and creates a lot of chances of other infectious ailments such as microbial and inflammation which is an awful situation for the patients3, so, there is significant need to develop an effective and safer drug. Hence on viewing the above situation, the synthesized transition metal complexes of hydrazone ligands were analyzed against anti-TB, antimicrobial and anti-inflammatory activities, in the hope of getting a significant therapeutic agent.
The utilization of metal complexes for treatment of health problems is an ancient practice but the investigation of structural characteristics of inorganic complexes for medicinal chemistry has advanced significantly. The ability of metal-based drugs to penetrate the microbial membrane and bind with genetic materials (RNA/DNA) of these pathogenic microbes, is a critical feature. Currently, transition metal complexes are a celebrated class of medicinal chemistry to discover novel biological agents with desired medicinal requirements. First row transition metal complexes have high nucleobase ability, more DNA binding efficacy and also have higher receptor binding capability. So, by analyzing the current scenario of biomolecules and metals, we choose the Co(II), Ni(II), Cu(II) and Zn(II) metals for the present research because these are recognized as promising anti-infectious agents4 due to their structural versatility, low toxicity, chelation, solubility effect, enzymatic action, interaction with proteins, high penetrating power, permeability, lipophilic character etc. Among the ligand scaffolds, researchers paid specific attention toward hydrazone ligands because of their well-known structural adaptability, chelating ability and wide variety of medicinal properties5. Thus, the metal complexes of hydrazone ligand are also broadly studied in medicinal chemistry with the purpose to discover a safe and effective therapeutic drug to cure numerous pathogenic diseases. Literature shows that these metal complexes have numerous pharmaceutical applications such as antimicrobial6, anti-TB7,8, anticancer9,10, antioxidant11, anti-inflammatory12, antimalarial13 etc. Further, the medicinal chemist faces a lot of problems to develop an effective drug with minimal disadvantages, therefore, in silico studies are worth mentioning to overcome these issues.
For ascertaining the binding nature of the ligands, structure of the complexes, purity, surface morphology, decomposition of the complexes etc., the various analytical studies were performed as mentioned below.
The surface morphology of the compounds was demonstrated using the SEM technique, which revealed that the hydrazone ligands and complexes have distinct surface morphology. The micrographs of ligand (1) and its [Co(L1)2(H2O)2] complex (3) are represented in Fig. 2 and have thread like morphology for ligand (1) while its complex (3) has rectangular bar like morphology. The reason behind difference in surface appearance of the ligands and complexes may be as a result of crystal aggregation and chelation of ligand with metal ion. Thus, SEM analysis supported the complex formation because the surface morphology of ligand was changed on complexation53.
The EDAX analysis evaluate the elemental compositions of the compounds as represented in Fig. 2. The numerous significant constitutes such as C, N, O, F were reported in micrograph of ligand (1) although the complex formation of ligand was clearly endorsed by emergence of Co(II) metal in micrograph of complex (3)54. So, EDAX data also authenticate the complexation process of ligands.
The inflammation is a leading reason of many serious ailments such as lungs problem, kidney failure, gastrointestinal disorder, heart failure etc. and also damage the heathy cells or organs during tuberculosis. The injuries, environmental problem, pathogen, radiations, medicinal allergy etc. are the main reasons behind the inflammation. Therefore, to cure the patient from these problems, we require an enriched anti-inflammatory drug which control the inflammation without any side effects. So, we carried out the BSA assay to examine the inflammation inhibition ability of the compounds. The obtained IC50 values are mentioned in Table S7 of supplementary and graphically represented in Fig. 5.
Lipophilicity is a significant physicochemical characteristic of biologically active compounds that influences their activity by playing a key role in the transport of compounds across biological membranes and in the creation of the ligand-receptor complex. The lipophilic nature of an active compound, defined as the ability of a compound to pass through hydrophobic barriers to reach the site of action from the delivery point. The tweedy chelation theory shows that the complexation increases the lipophilicity (supplementary Table S8) as well as hydrophobicity of the compounds which increased their biological activity.
So, the obtained results clearly state that the complex (10) has more potency against tuberculosis and behave as best 5V3Y inhibitors because it shows lowest binding score and good binding interactions, hence, it may be utilized in the place of standard drug for TB and its associated deformities.
The data used to support the findings of this study are included in the article and supplementary material. The datasets generated and/or analysed during the current study are available in the Worldwide Protein Data Bank (wwPDB) repository, [ ]. In addition, the other information can be made available by the corresponding author upon reasonable request as long as the request does not compromise intellectual property interests.
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Key processes of the global nitrogen cycle: dissimilatory nitrate reduction to ammonium (DNRA), denitrification, and nitrogen fixation; changes in the oxidation state of nitrogen, as well as in equations, are indicated by roman numerals
I did my Ph.D. work under the supervision of Peter Hemmerich [66] at the newly founded University of Konstanz, in an area of research nowadays called Bioinorganic Chemistry [67,68,69,70,71,72,73,74]. Hemmerich had fruitful collaborations with scientists from around the world: Helmut Beinert (Madison), Anders Ehrenberg (Stockholm), Jean-Marc Lhoste (Paris), Vincent Massey (Ann Arbor), Israel Pecht (Rehovot), Jack Spence (Logan), and Cees Veeger (Wageningen), to name a few. Advanced spectroscopic techniques, among them magnetic resonance methods as well as stopped-flow and rapid quench kinetics in the millisecond range, were established in Konstanz and applied to investigate the structure and function of complex flavin and metal-dependent enzymes. I started my work with two plant proteins, the blue multi-copper enzyme ascorbate oxidase and the type 1 Cu protein mavicyanin together with Augusto Marchesini (Milan) [75,76,77].
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