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. 2024 Jul 17;15(8):2785–2791. doi: 10.1039/d4md00221k

Expanding the chemical space of ester of quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential antitubercular agents†

Alonzo González-González a, Oscar Sánchez-Sánchez a, Baojie Wan b, Scott Franzblau b, Isidro Palos c, José C Espinoza-Hicks d, Adriana Moreno-Rodríguez e, Ana Verónica Martínez-Vázquez a, Edgar E Lara-Ramírez a, Eyra Ortiz-Pérez a, Alma D Paz-González a, Gildardo Rivera a,✉
PMCID: PMC11324059  PMID: 39149106

Abstract

Tuberculosis is a worldwide health problem that warrants attention given that the current treatment options require a long-term chemotherapeutic period and have reported the development of Mycobacterium tuberculosis (M. tuberculosis) multidrug resistant strains. In this study, n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide were evaluated against replicating and non-replicating H37Rv M. tuberculosis strains. The results showed that seventeen of the twenty-eight derivatives have minimum inhibitory concentration (MIC) values lower than isoniazid (2.92 μM). The most active antimycobacterial agents were T-148, T-149, T-163, and T-164, which have the lowest MIC values (0.53, 0.57, 0.53, and 0.55 μM respectively). These results confirm the potential of quinoxaline-1,4-di-N-oxide against M. tuberculosis to develop and obtain new and more safety antituberculosis drugs.

n-, and isobutyl esters of quinoxaline-1,4-di-N-oxide are effective anti-tuberculosis agents against replicating and non-replicating H37Rv bacilli, with top ten lead compounds being relatively safe with selectivity index values over 70.graphic file with name d4md00221k-ga.jpg

Introduction

Tuberculosis (TB) continues to be an important disease worldwide, as it is life-threatening, and has been for over a hundred years.1–3 The causative agent is a slow-dividing pathogen Mycobacterium tuberculosis (M. tuberculosis), a bacillus-type bacteria.4,5 In 2023, the World Health Organization (WHO) estimated 10.6 million of people infected, and approximately 1.3 million deaths worldwide.6

There is a treatment available for TB, which requires a long-term chemotherapeutic period; however, drug resistance has been developed.6,7 Of particular interest is the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains to first line drugs as isoniazid, rifampicin, and streptomycin7,8 as well as latent M. tuberculosis infection.9 Thus, there is a need to explore new more effective drug alternatives to circumvent the MDR, and XDR M. tuberculosis profiles.10

During the last five years various important efforts have been made to propose candidates, exploring heterocycles and hybrids as relevant structures to develop new antituberculosis agents, and combination therapies.11–17 Several important contributions have been achieved by these studies including the emergence new approved MDR, and XDR drugs bedaquiline, delamanid, linezolid, and pretonamid.11,12,14

Quinoxaline derivatives have been studied and found to possess a wide array of biological activities and medicinal chemists continue to study this scaffold to better understand their biological activities.18 Among these activities, antitubercular activity may be highlighted and warrant further studies,13,15,17,19 even the clofazimine (Fig. 1 top) quinoxaline derivatives currently being used as a second-line drug for MDR-TB.20,21

Fig. 1. Structures of previously reported quinoxaline derivatives with antimycobacterial activity, quinoxaline ring (red), 7-ester group (blue), including approved drug clofazimine.

Fig. 1

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Different substitutions for the 6, and 7 positions have been tested as modifications for the quinoxaline ring to attain antimycobacterial agents, these include methyl, and methoxy groups, as well as chlorine and fluorine atoms. Derivatives from these studies have shown important antimycobacterial activity, still, there is room for improvement. An example of alternatives is described in a study in 2018, where Palos et al. demonstrated that 7-ester-quinoxaline-1,4-di-N-oxide derivatives can be used as antituberculosis agents,13Fig. 1 presents the structures of the most active antimycobacterial agents in that study showing a tendency where longer and branched alkyl chains at 7-position lead to an increased activity. In the current study, we expand the current systematic approach of our research group by exploring the change in alkyl chain length at 7-position ester from a 1, 2 and 3-carbon chain tested by Palos to a 4-carbon alkyl chain, by testing n-butyl and isobutyl chains to assess the lengthening of the alkyl chain and the branching effect.

Results

Synthesis

Through the Beirut reaction,22 twenty-eight n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were synthesized and characterized by infrared (IR), proton and carbon nuclear magnetic resonance (1H-NMR and 13C-NMR), and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) (ESI†), for further biological evaluation.23

Anti-Mycobacterium tuberculosis evaluation

Replicating and non-replicating M. tuberculosis cells were treated with quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives to determine their antimycobacterial activity (Table 1) using modified Alamar blue microplate assay (MABA) and low-oxygen recovery assay (LORA) methodologies.

Anti-M. tuberculosis activity (MIC in μg mL−1) of n-butyl, and isobutyl quinoxaline-7-carboxylate-1,4-di-N-oxide derivatives.

graphic file with name d4md00221k-u1.jpg
Code R2 R3 R7 M. tuberculosis H37Rv Cytotoxicity (macrophages J774.2) (MIC μM)
MABA (MIC μM) LORA (MIC μM)
T-137 –CH3 –CH3 CH 3 (CH 2 ) 3 – 0.88 2.30 58.39
T-138 –OCH3 –CH3 CH 3 (CH 2 ) 3 – 0.87 5.24 46.24
T-139 –OCH2CH3 –CH3 CH3(CH2)3– 1.38 6.24 >200
T-140 –OC(CH3)3 –CH3 CH3(CH2)3– 14.73 127.93 >200
T-141 –OCH2 C6H5 –CH3 CH3(CH2)3– 0.59 1.73 >200
T-142 –C6H5 –CH3 CH3(CH2)3– 1.95 5.37 17.65
T-143 –HN–p-C6H4Cl –CH3 CH3(CH2)3– >116.55 >116.55 50.28
T-144 –NH–[2,4(CH3)2C6H3] –CH3 CH3(CH2)3– >118.20 >118.20 ND
T-145 –CH3 –CF3 CH 3 (CH 2 ) 3 – 0.62 0.97 >200
T-146 –OCH2CH3 –CF3 CH3(CH2)3– 0.57 0.87 >200
T-148 –C6H5 –CF3 CH 3 (CH 2 ) 3 – 0.53 0.88 48.37
T-149 –C4H3S –CF3 CH 3 (CH 2 ) 3 – 0.57 0.86 ND
T-150 –C10H7 –CF3 CH3(CH2)3– 1.07 3.04 >200
T-151 –NH–C6H5 –C6H5 CH3(CH2)3– 3.30 9.74 44.14
T-155 –CH3 –CH3 (CH 3 ) 2 CHCH 2 – 0.94 1.82 87.22
T-156 –OCH3 –CH3 (CH 3 ) 2 CHCH 2 – 0.84 2.01 ND
T-157 –C6H5 –CH3 (CH3)2CHCH2– 0.95 2.68 34.22
T-158 –NHC6H5 –CH3 (CH3)2CHCH2– 2.56 2.73 >200
T-159 –NH–[2,4(CH3)2C6H3] –CH3 (CH3)2CHCH2– 19.67 12.34 >200
T-161 –HN–p-C6H4Cl –CH3 (CH3)2CHCH2– 1.63 1.86 ND
T-163 –C6H5 –CF3 (CH 3 ) 2 CHCH 2 – 0.53 0.92 ND
T-164 –C4H3S –CF3 (CH 3 ) 2 CHCH 2 – 0.55 0.77 43.85
T-165 –C4H3O –CF3 (CH3)2CHCH2– 0.68 1.65 81.84
T-166 –C10H7 –CF3 (CH3)2CHCH2– 1.38 2.33 ND
T-167 –CH3 –CF3 (CH 3 ) 2 CHCH 2 – 0.70 0.94 25.4
T-168 –CH3 –C6H5 (CH3)2CHCH2– 0.71 1.82 28.53
T-169 –NHC6H5 –C6H5 (CH3)2CHCH2– 0.57 1.49 >200
T-170 –CH3 –NH–[2,4(CH3)2C6H3] (CH3)2CHCH2– >118.20 >118.20 >200
Rifampicin 0.02 0.06 ND
Isoniazid 2.92 >933.35 ND
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Cytotoxic evaluation

The series were determined their cytotoxic evaluation against macrophages J774.2 ATCC TIB-67 (Table 1) and the compounds showed half maximal cytotoxic concentration (CC50) values from 17.65 to over 200 μM. The selective index (SI) values (10.16–351) for antimycobacterial over cytotoxic activity against macrophages, proposing them as safe compounds at the needed concentration to exert their activity against M. tuberculosis.

Discussion

Structure–activity relationship analysis

The n-butyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives had MIC values in the range of 0.53 to 118.20 μM; ten of the fourteen n-butyl derivatives were more active (MIC 0.53–1.95 μM) than the reference drug isoniazid (MIC 2.92 μM). These compounds have aliphatic ketones (T-137, and T-145), esters (T-138, T-139, T-141, and T-146), and aromatic ketones (T-142, T-148, T-149 and T-150) at the 2-position, and most contains trifluoromethyl group at the 3-position, suggesting that the electron-withdrawing effect of the latter is important for antimycobacterial activity. Others substitutions that favours the biological activity are: 1) the change of methyl to trifluoromethyl at the 3-position in T-139vs.T-146 and T-142vs.T-148 leads to a 2.4-, and 3.7-fold increase in activity respectively, still the methyl substituted retain moderate activity which further emphasizes the importance of the ethyl ester and phenyl ketone at the 2-position respectively; 2) the change of phenyl to a naphthyl ring at the 2-position in derivatives T-148vs.T-150 results in a 2-fold decrease in activity suggesting that the steric effect plays a role, where bulkier ketones at the 2-position lead to a decreased activity. The most evident reduction in antimycobacterial activity is observed for the compound T-140 with a branched ester and compounds T-143, T-144, and T-151 with a benzamide group at the 2-position, suggesting that these types of substitution are detrimental to antimycobacterial activity. However, it should be noted that when comparing T-143 and T-144 (MIC > 116.5, and 118.2 μM respectively) vs.T-151 (3.30 μM) the latter is >30-fold more active, suggesting the benefit of the phenyl ring at the 3-position.

Analyzing the LORA results, a similar biological behaviour was observed as H37Rv, which suggests that this same SAR analysis describes favourable substitutions against non-replicating persistent (NRP) strain.

The isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives had MIC values in the range from 0.53 to 118.20 μM; eleven of fourteen isobutyl derivatives were more active (MIC 0.53–1.63 μM) than the reference drug isoniazid (MIC 2.92 μM). These compounds have aliphatic ketones (T-155, and T-167), ester (T-156), unsubstituted benzamide (T-169), substituted benzamide T-161, and aromatic ketones (T-157, T-163, T-164, T-165, and T-166,) at 2-position, and most contains trifluoromethyl group at 3-position, highlighting the importance of this group for the increased activity.

The change from phenyl (T-163) to naphthyl (T-166) leads to a 2.6-fold decrease in activity, as in the activity of their n-butyl analogues. The least active compounds had benzamide at the 2-position, which is consistent with the behaviour observed in the n-butyl series, as well as (Palos et al. 2018).13 Within this group of compounds containing a benzamide, it was observed that chlorine substitution (T-161) favoured activity slightly, whereas dimethyl substitution (T-159) lowered activity, compared to unsubstituted derivative (T-158), additionally the comparison of T-158vs.T-169 showed an increase in activity going from methyl to phenyl at the 3-position, supporting the potential benefit of phenyl at the 3-position when comparing T-143, T-144, and T-151 of the n-butyl series.

The isomer effect for T-157vs.T-168 only slightly favours the bulkier phenyl at the 3- over 2-position, yet, for T-159vs.T-170, there is a 6-fold increase going from one isomer to the other, still neither T-159 nor T-170 are better than the reference drug isoniazid. Analyzing the LORA results, a similar biological behaviour was observed to H37Rv, which suggests that this same SAR analysis describes favourable substitutions against the NPR strain. A summary of SAR analysis is shown in Fig. 2.

Fig. 2. Structure–activity relationship summary for antimycobacterial activity.

Fig. 2

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A comparative analysis of n-butyl and isobutyl series was done to determinate the effect at the 7-position on the quinoxaline 1,4-N-oxide ring, there are ten analogues for n-butyl and isobutyl series, five of them have a negligible effect, while the remaining are favoured by the branched analogue. The comparison of T-142vs.T-157, the branched derivative is two times more active for both H37Rv and NPR strains; for T-138vs.T-156, the branched analogue is two times more active for the NPR strain. The most significant changes occurred for the benzamide derivatives: for T-151vs.T-169, the branched analogue is ∼6-fold more active for both H37Rv and NRP strains; for T-144vs.T-159, the branched analogue is >6-fold more active than H37Rv, and >10-fold more active than NRP strain; finally, the most evident change is observed for T-143vs.T-161 where the branched analogue is >60-fold more active for both H37Rv and NRP strains, still it is only slightly better than reference drug isoniazid. Extending this comparison to the study of Palos et al. the effect of the extension of the chain shows a variable effect on antimycobacterial activity. For derivatives T-137, and T-155 which bear smaller groups acetyl, and methyl at 2-, and 3-position the comparison made with the direct analogs with 7-methyl, propyl, and isopropyl shows that the chain elongation permits an increase in antimycobacterial activity of replicative bacilli 2.8 to 11.2-fold, while for short chain (methyl and ethyl) esters T-138, T-139, and T-156 this change is variable, for the methyl ester derivative the change from 7-methyl and 7-isopropyl to butyl or isobutyl results in an increase in activity (1.13 to 2.15-fold), and for 7-propyl to butyl or isobutyl results in a decrease in activity (1.91 to 1.98-fold); for the ethyl ester derivative the change from 7-methyl or 7-ethyl to butyl or isobutyl is a negligible decrease, while for 7-propyl or 7-isopropyl to butyl or isobutyl results in a slight increase (1.52 to 1.74-fold). While maintaining methyl group at 3-position and having bulky groups (tert-butyl, and phenyl ring) at 3-position such as derivatives T-140, T-142, and T-157 the chain elongation at 7-position permits an important increase in antimycobacterial activity: for T-140 (bearing tert-butyl) the change from propyl to butyl chain permits an increase of 12.86-fold; for T-142 and T-157 (bearing phenyl) the change from methyl, ethyl, propyl, and isopropyl results in an increase ranging from 3.22 to 13.2-fold. For derivatives T-145 and T-167 the change from the 7-ethyl analogs was negligible, for 7-propyl analogs the change is favorable, over 11-fold more active, and for 7-isopropyl is detrimental, over 1.58-fold less active, The effect of the change at 7-position from propyl to butyl for derivative T-146, which bears a ethyl ester at 2-position and a trifluoromethyl at 3-position, is a 13-fold increase in activity altogether suggesting that for small groups at 2-position the increase in bulkiness at 7-position permits an increase in activity. In the case of derivatives with aromatic rings at 2-position and trifluoromethyl group at 3-position two effects are observed: 1) for phenyl at 2-position derivatives T-148, and T-163 the change from 7-propyl and isopropyl to 7-butyl and isobutyl results in over 5-fold increase, and for furyl at 2-position T-165 the change from 7-propyl and isopropyl to 7-isobutyl results in a 10.4- and 2.5-fold increase in antimycobacterial activity, 2) for naphthyl and thienyl at 2-position, derivatives T-149, T-150, T-164, and T-166 the chain elongation is clearly detrimental, 1.96 to 4.45-fold less active, suggesting that the increase in bulkiness to an already bulky molecule is counterproductive. For derivative T-158 which bears an unsubstituted benzamide at 2-position and a methyl at 3-position the change from 7-propyl and isopropyl to 7-isobutyl results in a 12.6- and 20.5-fold increase respectively. Altogether, the general tendency is that an increase in chain length for the ester at 7-position has a favorable effect on the antimycobacterial activity, except for derivatives containing already bulky substituents (naphthyl and thienyl) at 2-position. For most cases the chain elongation at 7-position resulted in an increase 2- to 10-fold in cytotoxicity in comparison to the molecules reported by Palos et al.

The comparison of our derivatives with previously reported quinoxaline-1,4-di-N-oxide not containing an ester at 7-position, evaluated using the same M. tuberculosis stain (H37RV), and under the same assay type MABA, shows that they perform well. The study by Jasso et al. in 2003, which reported their best compound was 2-acetyl-3-methylquinoxaline derivatives with chloride, methyl, and methoxide substitutions at the 6-, and 7-positions showed MIC values ranging from 1.36 to 13.49 μM.24 These results emphasize the benefit of 2-acetyl and 3-methyl substitutions, which is consistent with our findings, as T-137, and T-155 have these substitutions and are among the most active compounds of our study with MIC values of 0.88, and 0.94 μM respectively, comparable, and even better than Jasso's study. Furthermore, the study by Villar et al. in 2008 that tested the effect of ketones and amides at the 2-position provides further support for the benefit of ketones over amides at the 2-position, as in our study this effect is observed, the amide-substituted quinoxalines have the lowest antimycobacterial activity.25 Additionally, this comparison allowed support for the benefit of ester substitution at the 7-position, as the substitutions were the same as those reported by Jasso, and the observed MIC values range from 3.10 to 18.22 μM, a lower activity than most of our reported derivatives. Ancizu et al. in 2010 expanded the testing of amides at the 2-position, considering a 1 or 2 methylene spacer groups between nitrogen atom and phenyl ring achieving MIC values from 0.499 to 1.44 μM for the top ten compounds, all of which contain halogens or halogenated groups at the 6-, and 7-positions, which emphasize the benefits of the presence of halogens in the molecule to enhance antimycobacterial activity, still our derivatives fare well in comparison.26 The study conducted by Torres et al. in 2011 with 2-benzamide, and 2-hydrazide-3-methylquinoxaline-1,4-di-N-oxide derivatives showed the top five compounds with MIC values in the range of 1.07 to 2.57 μM, less active than most of our derivatives, supporting our choice of ketones and esters at the 2-position instead of benzamides.27 It is interesting to note that in recent years, quinoxaline-1,4-di-N-oxide has continued to be studied as a scaffold in the preparation of antimycobacterial agents, and our compounds perform well compared to these. In the same year Zhang et al. reported a series of thiazolidinone-quinoxaline-1,4-di-N-oxide hybrids with important antimycobacterial activity, their lead compounds showed MIC values of 3.83 to 4.16 μM, over 7-fold less active than our lead molecules.28 In both cases, its 6 and 7-positions were either not substituted or substituted with halogens, methyl, or methoxide, further supporting our proposal that esters at the 7-position favours antimycobacterial activity.

The overall tendencies observed for the n-, and isobutyl derivatives of quinoxaline-1,4-di-N-oxide esters is that generally they increase in activity with the presence of electron-withdrawing substituents, e.g. trifluoromethyl, this follows on a similar pattern to reports of antimycobacterial agents containing this scaffold.29 As suggested by several authors, this behaviour seems to be correlated to how readily the quinoxaline-1,4-di-N-oxide derivatives can be reduced when they bear electron-withdrawing substituents, consequently releasing reactive oxygen species (ROS) which in turn may be related to the antimycobacterial activity.29,30 Thus, a suggested mode of action for these derivatives may be related to the action of ROS on M. tuberculosis bacilli, as is the case for other reported quinoxaline-1,4-di-N-oxide derivatives. As reduction of quinoxaline derivatives may occur at hypoxic conditions,29 ROS generation and subsequent bacilli damage may serve to explain the activity on latent M. tuberculosis.

Materials and methods

N-butyl and isobutyl quinoxaline-7-carboxylate-1,4-di-N-oxide

The n-butyl and isobutyl quinoxaline-7-carboxylate-1,4-di-N-oxide derivatives (from T-137 to T-170) were synthesized using the Beirut reaction (Fig. 3) as described by González-González et al., through the reaction of the corresponding diketone (10.6 mmol) with the appropriate benzofuroxane N-oxide (2.4 mmol) in dry chloroform (35 mL). Triethylamine (TEA) was added (1 mL) and the reaction mixture was stirred at room temperature for 4–7 days.23 Reaction was monitored by thin-layer chromatography (TLC) in silica gel 60 coated plates (PF-245, Merck; Tokio, Japan), 0.25 nm thickness. Resulting plates were observed under UV light 254–265 nm. Purification was carried out in column chromatography using varying concentrations of hexane: ethyl acetate in a 2 mL gradient until compound elution. The infrared (IR) spectra were obtained using a PLATINUM-ATR Bruker Alpha FT-IR spectrometer. The 1H-NMR spectra were obtained in DMSO-d6 with trimethyl silane (TMS) as internal standard on a 400 MHz Bruker Advance III spectrometer (AXS Inc., Madison, WI, USA). Ultra-performance-liquid-chromatography analysis was carried out in a UPLC/MS (Acquity H UPLC® CLASS, Waters) using a 2.1 × 100 mm (ACQUITY UPLC® BEH C18 1.7 μm) column with running conditions of 1 μL sample injection, formic acid 0.1% (v/v water)-acetonitrile (30 : 70) mobile phase, 5 min per run and pressure from 0–15 000 psi.

Fig. 3. Beirut reaction scheme for the formation of quinoxaline-1,4-di-N-oxide derivatives from benzofuroxan-1-N-oxide and β-diketone.

Fig. 3

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Biological activity

The antimycobacterial activity (MIC values) was evaluated in vitro against M. tuberculosis strain H37Rv following MABA protocol.25 Assays were performed in triplicate independent experiments. The standard M. tuberculosis strain H37Rv was tested with known reference drugs rifampicin and isoniazid. The lowest drug concentration affecting an inhibition of 90% was considered as MIC. In addition, a LORA in vitro test was performed following the procedure reported by Cho et al. (2007).31

Cytotoxic activity

The murine macrophage cell line J774.2 was maintained in culture flasks with RPMI 1640 medium supplemented with 10% FBS, 1% MEM-NEAA medium (Gibco) and 100 U mL−1 antibiotic–antifungal mixture (Gibco). Cells were incubated at 37 °C with 5% CO2 and humidity. Macrophages were washed and viability was assessed by the MTT colorimetric assay. In a 96-well microplate, 1 × 105 macrophages were added per well and a dose–response assay was performed. Compounds were evaluated using serial to determine CC50 values in triplicate considering 0.1% DMSO as negative control.

Conclusions

In this study, twenty-eight n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivates were tested as new antimycobacterial agents. Seventeen compounds had MIC values (0.23–0.36 μg mL−1) better than the reference drug isoniazid (2.92 μM), with the best antimycobacterial activity observed for eight compounds with MIC ≤ 0.62 μM (T-141, T-145, T-146, T-148, T-149, T-163, T-164, and T-169). SAR analysis showed that antimycobacterial activity is favoured by acetyl, single-ring aromatic ketones and esters at the 2-position, and trifluoromethyl at the 3-position, and except for T-169 reduced by the presence of amides at the 2-position. Additionally, there is no difference between the pattern observed for the antimycobacterial effect of the quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives against replicating and non-replicating M. tuberculosis strains. Finally, the n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives may continue to be explored, with a degree of safety expected from them, supported by cytotoxicity analysis showing over 10-times more activity against M. tuberculosis over J774.2 macrophages.

Data availability statement

The data here presented can be openly shared upon in the ESI† or request to the corresponding author: giriveras@ipn.mx.

Author contributions

Conceptualization, G. R. and A. G. G; methodology, A. G. G, O. S. S, S. F., B. W., I. P., A. V. M. V., E. E. L. R., A. D. P.-G., J. C. E. H. A. M. R,; software, A. G. G; validation, G. R., and A. G. G; formal analysis, A. G. G, and G. R; investigation, A. G. G, O. S. S; resources, G. R.; data curation, G. R, and E. E. L. R; writing—original draft preparation, A. G. G, and G. R.; writing—review and editing, A. G. G, O. S. S, S. F., B. W., A. V. M. V., A. M. R, E. E. L. R., J. C. E. H., and G. R.; visualization, A. G. G, and G. R.; supervision, G. R, and S. F.; project administration, G. R.; funding acquisition, G. R. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Supplementary Material

MD-015-D4MD00221K-s001

Acknowledgments

This research was supported by Secretaria de Investigacion y Posgrado del Instituto Politécnico Nacional, grant numbers: Proyecto SIP 20230935 and SIP 20240460.

†

Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4md00221k

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

MD-015-D4MD00221K-s001
MD-015-D4MD00221K-s001.pdf (11.2MB, pdf)

Data Availability Statement

The data here presented can be openly shared upon in the ESI† or request to the corresponding author: giriveras@ipn.mx.

Articles from RSC Medicinal Chemistry are provided here courtesy of Royal Society of Chemistry

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