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Cited by 3 publications
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Copper- and Ligand-Free Sonogashira Cross-Coupling: Access to Novel 3-Aminoindole Derivatives and Their Biological Evaluations
Indole-containing compounds are widely distributed in the plant and animal kingdom, and their biological activity and pharmacological properties have prompted research into their chemical properties. This study developed a one-pot methodology for the synthesis of 3-aminoindole derivatives using copper- and ligand-free Sonogashira cross-coupling reaction conditions. The synthesised 3-aminoindole derivatives were confirmed using spectroscopic techniques. The resulting 3-aminoindole derivatives were biologically evaluated against Mycobacterium tuberculosis and Plasmodium falciparum. For example, indole derivatives 10a (7.813 µM) and 10j (8.332 µM) were the most active derivatives in the CAS and ADC media, respectively.
Copper- and Ligand-Free Sonogashira Cross-Coupling: Access to Novel 3-Aminoindole Derivatives and Their Biological Evaluations
Indole-containing compounds are widely distributed in the plant and animal kingdom, and their biological activity and pharmacological properties have prompted research into their chemical properties. This study developed a one-pot methodology for the synthesis of 3-aminoindole derivatives using copper- and ligand-free Sonogashira cross-coupling reaction conditions. The synthesised 3-aminoindole derivatives were confirmed using spectroscopic techniques. The resulting 3-aminoindole derivatives were biologically evaluated against Mycobacterium tuberculosis and Plasmodium falciparum. For example, indole derivatives 10a (7.813 µM) and 10j (8.332 µM) were the most active derivatives in the CAS and ADC media, respectively.
Benzylated Sulfamethoxazole Derivatives with Improved Safety Profile as Potential Anti-Mycobacterium tuberculosis and Antibacterial Agents
This study focussed on the synthesis of sulfamethoxazole derivatives and their biological evaluation. The sulfamethoxazole derivatives were successfully biologically evaluated against Mycobacterium tuberculosis, Staphylococcus aureus, and Chinese Hamster Ovarian (CHO) cells. The biological evaluation revealed compounds with improved antitubercular activity and antibacterial activity against S. aureus as well as safety profile when compared to the starting material, sulfamethoxazole. The most active compounds against Mycobacterium tuberculosis were3q with 92% inhibition followed by 3s (90%), 3k (88%), 3t (85%), and 3o (84%).
Aim: Synthesis and biological evaluation of benzylamine derivatives against Mycobacterium tuberculosis (Mtb) H37Rv strain. Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors to ill health in the world. TB is considered the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), the global number of deaths associated with TB has been slowly declining with 1.3 million reported in 2016 and 2017, and 1.2 million reported in 2018 and 2019 [1–4]. Unfortunately, WHO also reported that the number of people infected with TB has increased from 6.4 million in 2017 to 7.1 million in 2019 [4]. Although significant progress has been achieved towards the development of antitubercular drugs, the emergence of multidrug-resistance tuberculosis (MD-R TB) and extensively drug-resistance tuberculosis (XDR-TB) coupled with the time required to completely cure tuberculosis (3 – 9 months) has compromised the management of tuberculosis. This compromise has led to the inefficient use of the first-line TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin) mainly due to the development of resistance towards these drugs [5–11]. To solve the resistance towards first-line TB drugs, intensive research efforts were directed at finding efficient and better-acting TB drugs. These efforts led to the development of antitubercular drugs such as bedaquiline [12], linezolid [13], delamanid [14] and pretonamid [15] (Fig. 1) as drugs that were aimed at treating MDR-TB and XDR-TB. Despite the successful introduction of these drugs to treat TB, there are still more challenges that need to be addressed. Some of these challenges include treatment of people with HIV co-infection [16], shortened treatment time and drug costs [17], complicated regimen (number of pills required for the successful treatment) [18], effective and early TB detection [19], suitability of the current drugs for children (pill vs syrup) [20] and the emergence of totally-drug resistance TB (TDR-TB) strain [21]. Therefore, solving some or all these challenges will help WHO in meeting its goals of significantly reducing the burden of TB and subsequently, the reduction of the death toll associated with TB by 90% in 2030 [4]. More intensified research efforts are underway to identify novel methods and drugs for the treatment of TB. For example, studies of high doses of rifapentine as a replacement for rifampin for the shortened treatment time [22] while nanoparticles-based treatment is being explored for directed treatment [23, 24]. Benzylamine-containing compounds have been studied as potential drugs for treating an array of diseases including TB [25]. These investigations include their use as Kallikrein 5 inhibitors [26], Toll-Like Receptor 2 inhibitors [27], antifungal and antibacterial agents [28], possible anticancer agents [29, 30] and antidiabetic agents [31]. In addition to the above-mentioned biological properties, several drugs containing benzylamine have been approved for different ailments. For example, Levocetirizine is used for the treatment of hay fever, Clopidogrel is used as an antiplatelet drug to reduce the risks of heart disease and stroke, Donepezil is used for the treatment of Alzheimer’s disease while Mirtazapine is used for the treatment of depression (Fig. 2) [32]. Taking advantage of the remarkable biological properties of benzylamine-containing compounds, here, we report the synthesis of benzylamine derivatives as potential antituberculosis agents. Halogens (iodine and bromine) were introduced on position 5 of the benzylamine to investigate their effect on the properties of the synthesised compounds. The benzylamine derivatives were biologically evaluated (in vitro) against Mtb H37RV strain while their cytotoxicity was on the Chinese Hamster ovarian (CHO) cell line. Objective: Taking advantage of the remarkable biological properties of benzylamine-containing compounds, here, we report the synthesis of benzylamine derivatives as potential antituberculosis agents. Method: General Information: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received unless otherwise stated. The structural properties of the compounds were recorded and confirmed by: High-resolution mass spectra were recorded using Sciex X500R QTOF at the University of Limpopo Mass Spectrometry Facility; Melting points were obtained using Lasec/SA-melting point apparatus from Lasec company, SA (Johannesburg, South Africa); IR spectra were recorded using Bruker technologies Alpha Platinum ATR FTIR spectrometer; and Nuclear Magnetic Resonance (NMR) (Bruker Ascend 400 MHz Topspin 3.2). 1H NMR and 13C NMR spectra were referenced internally using solvent signals, 1H NMR: 7.250 ppm for CDCl3, 2.500 ppm for DMSO-d6; 13C NMR: 77.00 ppm for CDCl3, 39.40 ppm for DMSO-d6, which were used as the solvents at room temperature. Chemical shifts are expressed in δ-values parts per million (ppm) and the coupling constants (J) in Hertz (Hz). The multiplicity of the signals is given as follows: brs = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet and m = multiplet. Result: Chemistry: To access the compounds with antitubercular properties, 3-ethoxysalcyladehyde 1 served as the starting point of the investigations. The investigation started by brominating the starting material using N-bromosuccinimide (NBS) according to the reported synthetic method. This method was also used for the iodination of the starting material using N-iodosuccinimide (NIS) resulting in the formation of products 2 and 3, respectively [33]. Reductive amination is a very useful synthetic method that was used to access pharmaceutical drugs used in the treatment of various diseases such as cancer, diabetes, fungal infections and many more [34]. Compounds 1 – 3 were treated with various aromatic amines under reductive amination reaction conditions using sodium borohydride in methanol to yield benzylamine derivatives as shown in Scheme 1 [34]. Compounds 1a – n were synthesised by treating 3-ethoxysalcyladehyde 1 with various aromatic amines and were obtained in good to excellent yields. The 1H NMR spectra of the compounds showed the disappearance of the aldehyde signal around 10 ppm and the appearance of the methylene signals ranging from 3.93 – 4.68 ppm in addition to other proton signals from the aromatic amines. To supplement the 1H NMR spectroscopy, the 13C NMR spectra were recorded. The 13C NMR spectra of 1a – n showed the disappearance of the aldehyde signal around 196 ppm and the appearance of the methylene signals in the region of 43.04 – 52.57 ppm. The same aromatic amines used in the synthesis of compounds 1a – n were also used for the construction of compounds 2a – k and 3a – l and thus displayed similar NMR spectroscopic characteristics. For example, in the case of compounds 2a – k 1H NMR spectra, methylene signals appeared in the region of 3.88 – 4.39 ppm while compounds 3a – l showed methylene signals ranging from 3.83 ppm to 4.36 ppm. The 13NMR spectra signals of the methylene group appeared between 42.66 and 52.40 ppm for compounds 2a – k and between 42.25 and 52.60 ppm for compounds 3a – l. The successful synthesis of all the compounds was confirmed by both 1H and 13C NMR, IR and mass spectroscopy. Biological Evaluation: All the synthesised compounds were evaluated for their biological activity against Myocobacterium tuberculosis (Mtb) H37RV strain. The biological assays were performed following a broth dilution method in 7H9_ADC_GLU_TW (7 days) and rifampicin was used as a positive control [35]. The results for the in vitro biological assays are displayed in Table 1. The biological assay results in Table 1 indicate that all compounds possessed activity against Mycobacterium tuberculosis with MIC90 values ranging from 20.04 (most active) – > 125 µM (least active). Only one compound, 2f was considered ineffective with MIC90 value >125 µM. Other compounds in this series exhibited better activity with MIC90 values of < 30 µM. The most active compounds in this series, 2c and 2e exhibited MIC90 values of 20.04 µM, representing the most active compounds for 2-fluorophenyl and 2-methoxyphenyl substituents, respectively. When phenyl, benzyl, 2-picolyl and 2-iodophenyl were used as substituents, the most active compounds were 2a (22.26 µM), 2b (20.59 µM), 1c (20.44 µM) and 3e (20.29 µM), respectively. The use of ortho-substituted phenyl reagents has produced some of the most active compounds in the series while the use of para-substituted phenyl reagents produced compounds with reduced activity against Mycobacterium tuberculosis. For example, 2f with 4-fluorophenyl substituent was inactive, 2g with 4-iodophenyl substituent exhibited an activity of 20.39 µM while 4-methoxypheyl (3i) had an activity of 21.89 µM. The reduced activity against Mtb was further observed when some disubstituted phenyl reagents were used. Compound 3j displayed an activity of 21.54 µM, compound 1k showed an activity of 21 µM and compound 3k had the best activity at 21.84 µM. These MIC90 values are slightly lower than those obtained for ortho and para-substituted phenyl derivatives. Notably, 5-fluoro-2-iodophenyl and 3,5-dichlorophenyl substituents displayed MIC90 values comparable to those of ortho substituted phenyl substituents. The most active compounds were 3l (20.59 µM), followed by compound 1m (20.64 µM) and lastly compound 1n (20.67 µM). In addition to the biological assays against Myocobacterium tuberculosis, cytotoxicity assays were also performed for all the compounds against Chinese Hamster Ovarian (CHO) cells to determine the concentration at which these compounds are likely to be toxic. Quantitative assessment of toxic activity in vitro was determined via the MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide] assay with emetine used as a standard [36]. The test compounds were largely non-toxic to CHO cells up to the highest concentration evaluated of 50 µM. Only two compounds, 3c (12.45 µM) and 3h (8.80 µM) showed moderate activity against the cells, with three other compounds (3d, 47.28 µM; 3i, 44.98 µM and 3j, 48.00 µM) showing low levels of toxicity. Interestingly, all the compounds showing weak to moderate activity against CHO cells contain iodo substituent at position 5 of the benzylamine. However, not all compounds containing 5-iodo substituent displayed toxicity towards CHO cells, indicating that the whole structure of the compound is likely responsible for the activity observed. Structure-activity Relationship and ADMET Predictions: The effect of substituents on the activity and cytotoxicity of the synthesised compounds was examined. Compounds containing 5-bromo substituent displayed the best activity against Myocobacterium tuberculosis. Notably, the activity of these compounds also depended on the type of substituents in the phenyl group. For example, ortho-substituted phenyl-containing compounds (2c, 2e) were the most active against Mtb with the exception of 2d which showed reduced activity. Although compounds containing 5-bromo substituent continued their activity against Mtb (2a, 2b, 2g), the only inactive compound in this study 2f with 4-fluorophenyl belonged to the 5-bromo substituent series. Compounds containing 5-iodo substituent displayed slightly reduced activity that largely depended on the substituents in the phenyl group. For example, compounds with 2-iodophenyl (3e), 4-fluorophenyl (3g), 4-methoxyphenyl (3i), 5-chloro-2-iodophenyl (3k) and 3,5-dichlorophenyl (3l) were the more active against Mtb in comparison to compounds containing no substituent (1e-n) and other 5-bromo substituted benzylamine derivatives (2e-k). Unfortunately, the series of compounds containing 5-iodo substituent produced the only compounds in this study that showed activity against CHO cells (3c, 3d, 3h, 3i and 3j). Physiochemical properties (Adsorption, Distribution, Metabolism, Excretion and Toxicity (ADMET)) of the synthesised compounds were analysed using the online prediction software ADMETlab 2.0.37,38 These physiochemical predictions will help in understanding the behaviour of the synthesised compounds after consumption and the results are displayed in Table 2. Analysis of Table 2 results revealed that only two compounds (1b, 1c) had the best predicted drug-like properties followed by 3b and 3c, which displayed poor predicted logP and clearance values, respectively. All compounds in this study displayed poor predicted half-life values. In general, the use of phenyl substituents with or without halogen substituents (Br, Cl, F, I) led to poor drug-like predicted properties (e.g. 1a, 1f). Notably, the compounds with the best predicted drug-like properties possessed a methylene bridge without halogen substituents (1a and 1b), thus, indicating its role in improving drug-like properties. All compounds satisfied Lipinski’s rule with the exception of compound 3k which also failed both Pfizer’s and GSK’s rules. In addition to 3k, several compounds (e.g. 2d, 3d, 3e and others) containing more than two halogen substituents (with the exception of 3f and 3i), failed both Pfizer’s and GSK’s rules. Finally, the predicted ADMET properties of Rifampicin, the approved antitubercular drug used as a reference showed a compound with favourable logP, logD and PPB values. However, Rifampicin was predicted to have high toxicity, poor clearance and half-life values, and it was also rejected by GSK’s rule. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of > 20 µM < 28 µM). The most active compounds, 2c and 2e possessed MIC90 values of 20.04 µM each. Compounds with 5-bromo substituent were the most active against Mtb. Cytotoxicity results revealed compounds largely inactive against CHO cells with the exception of 3c, 3d, 3h, 3i and 3j with 3i being the most active with an MIC50 value of 8.80 µM. Predicted ADMET properties of the synthesised compounds revealed that phenyl substituents and the presence of halogen substituents received unfavourable physiochemical properties while the introduction of methylene bridge received favourable physiochemical properties. This study has demonstrated the ability of benzylamine derivatives as possible future drug candidates for the treatment of tuberculosis.
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