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Article

ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity

by
Mashooq A. Bhat
1,*,
Ahmed M. Naglah
2,3,
Siddique Akber Ansari
1,
Hanaa M. Al-Tuwajiria
1 and
Abdullah Al-Dhfyan
4,5
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
2
Department of Pharmaceutical Chemistry, Drug Exploration and Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
3
Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, Dokki, Cairo 12622, Egypt
4
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
5
Stem Cell & Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital, MBC-03, P.O. Box 3354, Riyadh 11211, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(12), 3667; https://doi.org/10.3390/molecules26123667
Submission received: 30 December 2020 / Revised: 22 February 2021 / Accepted: 21 April 2021 / Published: 16 June 2021
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Abstract

:
A ChCl: Gly (DESs) promoted environmentally benign method was developed for the first time using the reaction of aryl aldehydes and dimedone to give excellent yields of xanthene analogues. The major application of this present protocol is the use of green solvent, a wide range of substrate, short reaction times, ease of recovery, the recyclability of the catalyst, high reaction yield, and ChCl: Gly as an alternative catalyst and solvent. In addition to this, all the synthesized compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Ra (MTB) and M. bovis BCG strains. The compounds 3d, 3e, 3f, and 3j showed significant antitubercular activity against MTB and M. bovis strains with minimum inhibitory concentration (MIC) values of 2.5−15.10 µg/mL and 0.26–14.92 µg/mL, respectively. The compounds 3e, 3f, and 3j were found to be nontoxic against MCF-7, A549, HCT 116, and THP-1 cell lines. All the prepared compounds were confirmed by 1H NMR and 13C NMR analysis.

1. Introduction

In the last few years, deep eutectic solvents (DESs) have emerged as ecofriendly and environmentally benign reaction protocols because of the exclusive physicochemical properties, including negligible vapor pressure, nontoxicity, relatively wide liquid range, biodegradability, and bio renewability [1,2]. DESs are easily prepared by the reaction of hydrogen bond donor compounds, such as urea, succinic acid, malonic acid, and zinc chloride with choline chloride as a quaternary ammonium salts. DESs also behave in a different way than their individual components. The melting point of DESs is less than their parent components due to charge delocalization occurring through hydrogen bonding between the hydrogen donor component and halide ion [3]. The glycerol acts as an efficient promoting medium for the electrophilic activation of aldehydes in the reaction [4]. Choline chloride-based DESs have been efficiently used for condensation reactions [5], benzylation of phenol [6], synthesis of spirooxoindole [7], Pictet–Spengler reaction [8], Clauson–Kaas reaction [9], Perkin reaction [10], N-alkylation of amines [11], synthesis of pyrroles and furans [8], isolation of residual KOH content from biodiesel [12], deacidification of palm oil [13], synthesis of highly substituted cyclohexa-1,3-dienamines [14], extraction of phenolic compounds from oil mixtures [15], extraction of vanillin [16], and pretreatment of rice straw for butanol fermentation [17].
Tuberculosis is the ninth leading cause of death worldwide from a single infectious agent, ranking above human immune deficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). It is a fatal airborne disease caused by Mycobacterium tuberculosis (Mtb), which affects the lung and is also responsible for infection in other sites of the body [18]. The global tuberculosis report of 2019 given by the World Health Organization (WHO) shows that TB is the leading cause of deaths due to antimicrobial resistance and among people with HIV [19]. More than half a million new TB cases were notified to WHO by national authorities [20]. Hence, the development of new therapeutic agents against TB is the urgent need of the time.
According to a literature survey, xanthene derivatives are endowed with various biological activities, including potent antimicrobial [21], analgesic [22], antimalarial [23], anti-inflammatory [24], antiviral [25], antioxidant [26], antiproliferative activity [27], anticancer [28], and urease activity [29]; inhibition of trypanothione reductase [23]; bone morphogenetic protein (BMP-2)-targeted osteogenic agents [30]; selective positive allosteric modulators of the δ-opioid receptors [31]; and estrogen receptors [32]. The structures of biologically active xanthene analogues are presented in Figure 1.
The expansion of a synthetic route for the synthesis of these biologically active compounds using a facile, environmentally benign and nontoxic catalyst is of enormous significance from the academic as well as industrial points of view. In the last few years, a large number of protocols have been developed by researchers, including sulfuric acid or hydrochloric acid [33], silica sulfuric acid [34], sulfamic acid [35], p-dodecylbenzenesulfonic acid [36], boric acid [37], p-toluene sulfonic acid (p-TSA) [38], NaHSO4-SiO2 [39], TiO2-SO42− [40], molecular iodine [41], amberlyst-15 [42], and cyanuric chloride [43]. However, a large number of the above routes have some drawbacks, such as the use of hazardous reagents, long reaction times, strong acidic conditions and lower yields of final products. Therefore, there is an urgent need for innovative and environmentally benign protocols to synthesize biologically active compounds with ease. Keeping in mind the pharmacological significance of xanthene derivatives and application of DESs for organic transformation, and in continuation of our work on the synthesis and bio evaluation of numerous compounds [44], herein, we report for the first time choline chloride: glycerol (ChCl: Gly)-based synthesis of xanthene derivatives in excellent yields. The synthesized products were evaluated for their antitubercular, cytotoxicity and antibacterial activities.

2. Materials and Methods

2.1. Preparation of ChCl: Gly

A mixture of ChCl (7.00 g, 50 mmol) and glycerol (11.65 g, 100 mmol) was added to a round-bottomed flask. The reaction mixture was stirred at 70 °C until the formation of colorless homogeneous liquid. This reaction follows the green chemistry rules [45].

2.2. General Procedure for Synthesis of Xanthene Derivatives

A mixture of benzaldehyde 1a (1 mmol) and dimedone 2 (1 mmol) in ChCl: Gly (2 mL) was stirred at a temperature of 80 °C. The progress of the reaction was monitored by thin-layer chromatography [n-hexane/ethyl acetate (3:7)] as a mobile phase. After completion of the reaction, the reaction mass was allowed to cool for 30 min and poured on ice-cold water. Thus, the solid compound obtained was filtered, dried out, and crystallized in ethanol to give the pure product. The synthesized compound was confirmed by m.p., 1H NMR, and 13C NMR.

2.2.1. 3,3,6,6-Tetramethyl-9-phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3a)

Compound 3a was obtained from condensation reaction 1a and 2 as a white solid; m.p.: 205–206 °C; Yield: 93%; 1H NMR (500 MHz, CDCl3) δ 11.93 (s, 1H), 7.29–7.26 (t, J = 7.6 Hz, 2H), 7.19–7.09 (m, 3H), 5.56 (d, J = 60.1 Hz, 1H), 2.49–2.30 (m, 9H), 1.24–1.11 (dd, J = 64.4, 29.0 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 195.65 (C=O), 164.07 (C=C-O), 143.16 (Ar-H), 135.05 (Ar-H), 129.49 (Ar-H), 127.51 (Ar-H), 119.84 (Ar-H), 50.45 (CH), 42.23 (CH2), 32.45 (CH2), 31.34 (CH2), 29.56 (CH3) and 29.33 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H27O3 [M+H]+, 351.0920: found: 351.0903.

2.2.2. 3,3,6,6-Tetramethyl-9-(m-tolyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3b)

Compound 3b was obtained from condensation reaction 1a and 2 as a white solid; m.p.: 208–210 °C; Yield: 86%; 1H NMR (400 MHz, CDCl3) δ 7.10–6.99 (m, 3H), 6.86 (d, J = 6.8 Hz, 1H), 4.68 (s, 1H), 2.44 (s, 4H), 2.24 (s, 3H), 2.20–2.10 (t, J = 13.8 Hz, 4H), 1.05 (s, 6H), 0.95 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.31 (C=O), 162.23 (C=C-O), 144.01 (Ar-H), 137.21 (Ar-H), 129.38 (Ar-H), 127.84 (Ar-H), 127.13 (Ar-H), 125.21 (Ar-H), 115.67 (Ar-H), 50.76 (CH), 40.84 (CH2), 32.17 (CH2), 31.68 (CH2), 29.24 (CH2), 27.30 (CH3) and 21.48 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C24H29O3 [M + H]+, 365.0650: found: 365.0673.

2.2.3. 3,3,6,6-Tetramethyl-9-(p-tolyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3c)

Compound 3c was obtained from condensation reaction 1c and 2 as a yellow solid; m.p.: 222–224 °C; Yield: 90%; 1H NMR (400 MHz, CDCl3) δ 7.15–7.14 (d, J = 7.8 Hz, 2H), 6.99–6.97 (d, J = 7.5 Hz, 2H), 4.68 (s, 1H), 2.43 (s, 4H), 2.20 (s, 3H), 2.17–2.09 (m, 4H), 1.06 (s, 6H), 0.95 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.36 (C=O), 162.17 (C=C-O), 141.21(Ar-C), 135.61(Ar-C), 128.71 (Ar-C), 128.20 (Ar-C), 115.67 (Ar-C), 50.75 (CH), 40.81 (CH2), 32.13 (CH2), 31.40 (CH2), 29.23 (CH2), 27.31 (CH3) and 21.02 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C24H29O3 [M + H]+, 365.5041: found: 365.5012.

2.2.4. 9-(3-Methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3d)

Compound 3d was obtained from condensation reaction 1d and 2 as a yellow solid; m.p.: 162–164 °C; Yield: 84%; 1H NMR (400 MHz, CDCl3) δ 7.05–7.01 (t, J = 8.1 Hz, 1H), 6.80–6.79 (d, J = 6.9 Hz, 2H), 6.57–6.55 (d, J = 7.0 Hz, 1H), 4.66 (s, 1H), 3.66 (s, 3H), 2.40 (s, 4H), 2.17–2.06 (q, J = 16.2 Hz, 4H), 1.01 (s, 6H), 0.91 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.26 (C=O), 162.35 (C=C-O), 159.26 (Ar-C), 145.68 (Ar-C), 128.77 (Ar-C), 120.72 (Ar-C), 115.42 (Ar-C), 114.26 (Ar-C), 111.78 (Ar-C), 55.01(OCH3), 50.70 (CH), 40.75 (CH2), 32.09 (CH2), 31.73 (CH2), 29.18 (CH3) and 27.29 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C24H29O4 [M+H]+, 381.1631: found: 381.1645.

2.2.5. 9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3e)

Compound 3e was obtained from condensation reaction 1e and 2 as a yellow solid; m.p.: 248–250 °C; Yield: 90%; 1H NMR (400 MHz, CDCl3) δ 7.17–7.15 (m, 2H), 6.71–6.69 (dd, J = 5.8, 2.6 Hz, 2H), 4.65 (s, 1H), 3.68 (d, J = 4.9 Hz, 3H), 2.42 (s, 4H), 2.20–2.09 (m, 4H), 1.05 (s, 6H), 0.94 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.40 (C=O), 162.05 (C=C-O), 157.90 (Ar-C), 136.47 (Ar-C), 129.25 (Ar-C), 115.72 (Ar-C), 113.41 (Ar-C), 55.05 (CH3), 50.74 (CH), 40.81 (CH2), 32.14 (CH2), 30.92 (CH2), 29.23 (CH3) and 27.29 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C24H29O4 [M+H]+, 381.1150: found: 381.1132.

2.2.6. 9-(3,4-Dimethoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3f)

Compound 3f was obtained from condensation reaction 1f and 2 as a yellow solid; m.p.: 200–202 °C; Yield: 89%; 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 6.75–6.68 (td, J = 8.2, 4.3 Hz, 2H), 4.68 (s, 1H), 3.83 (d, J = 1.8 Hz, 3H), 3.77 (d, J = 1.7 Hz, 3H), 2.44 (s, 4H), 2.24–2.14 (m, 4H), 1.09 (s, 6H), 0.98 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.42 (C=O), 162.08 (C=C-O), 148.44 (Ar-C), 147.45 (Ar-C), 136.98 (Ar-C), 120.09 (Ar-C), 115.73 (Ar-C), 112.31 (Ar-C), 110.85 (Ar-C), 55.85 (CH3), 50.74 (CH), 40.87 (CH2), 32.15 (CH2), 31.20 (CH2), 29.30 (CH3) and 27.14 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C25H31O5 [M+H]+, 411.2860: found: 411.2845.

2.2.7. 3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3g)

Compound 3g was obtained from condensation reaction 1g and 2 as a red solid; m.p.: 172–174 °C; Yield: 82%; 1H NMR (400 MHz, CDCl3) δ 8.01–7.95 (m, 2H), 7.79–7.77 (d, J = 6.7 Hz, 1H), 7.40–7.38 (d, J = 7.8 Hz, 1H), 4.81 (s, 1H), 2.49 (s, 4H), 2.25–2.12 (q, J = 16.3 Hz, 4H), 1.09 (s, 6H), 0.97 (s, 6H), 13C NMR (101 MHz, CDCl3) δ 196.30 (C=O), 162.98 (C=C-O), 148.32 (Ar-C), 146.26 (Ar-C), 135.72 (Ar-C), 128.76 (Ar-C), 112.48 (Ar-C), 121.64 (Ar-C), 114.53 (Ar-C), 50.62 (CH), 40.81 (CH2), 32.22 (CH2), 32.07 (CH2), 29.17 (CH3)and 27.29 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H26NO5 [M+H]+, 396.3451: found: 396.3469.

2.2.8. 9-(3-Iodophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3h)

Compound 3h was obtained from condensation reaction 1h and 2 as a pale yellow solid; m.p.: 276–278 °C; Yield: 84%; 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.42–7.41 (d, J = 7.8 Hz, 1H),7.32–7.24 (d, J = 7.6 Hz, 1H), 6.96–6.92 (t, J = 7.8 Hz, 1H), 4.60 (s, 1H), 2.45 (s, 4H), 2.24–2.14 (m, 4H), 1.08 (s, 6H), 0.99 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.21 (C=O), 162.48 (C=C-O), 146.36 (Ar-C), 137.07 (Ar-C), 135.48 (Ar-C), 129.76 (Ar-C), 128.20 (Ar-C), 115.05 (Ar-C), 94.07 (Ar-C), 50.67 (CH), 40.84 (CH2), 32.21 (CH2), 31.61 (CH2), 29.67 (CH2), 29.20 (CH3) and 27.32 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H26IO3 [M+H]+, 477.3570: found: 477.3526.

2.2.9. 9-(4-Bromophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3i)

Compound 3i was obtained from condensation reaction 1i and 2 as a red solid; m.p.: 238–240 °C; Yield: 86%; 1H NMR (400 MHz, CDCl3) δ 7.34–7.32 (d, J = 6.9 Hz, 2H), 7.18–7.16 (d, J = 6.8 Hz, 2H), 4.69 (s, 1H), 2.46 (s, 4H), 2.25–2.14 (q, J = 16.4 Hz, 4H), 1.10 (s, 6H), 0.98 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.26 (C=O), 162.41 (C=C-O), 143.18 (Ar-C), 131.09 (Ar-C), 130.13 (Ar-C), 120.18 (Ar-C), 115.14 (Ar-C), 50.65 (CH), 40.81 (CH2), 32.15 (CH2), 31.52 (CH2), 29.21 (CH3) and 27.26 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF):Calcd for C23H26BrO3 [M+H]+, 430.2450: found: 430.2400.

2.2.10. 9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3j)

Compound 3j was obtained from condensation reaction 1j and 2 as a yellow solid; m.p.: 238–240 °C; Yield: 90%; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 2H), 7.21–7.14 (m, 2H), 4.71 (s, 1H), 2.47 (s, 4H), 2.19 (q, J = 16.3 Hz, 4H), 1.10 (s, 6H), 0.98 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 196.28 (C=O), 162.44 (C=C-O), 142.70 (Ar-C), 131.93 (Ar-C), 129.74 (Ar-C), 128.13 (Ar-C), 115.18 (Ar-C), 50.66 (CH), 40.79 (CH2), 32.14 (CH2), 31.43 (CH2), 29.21 (CH3) and 27.24 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H26ClO3 [M+H]+, 385.1165: found: 385.1129.

2.2.11. 9-(4-Hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3l)

Compound 3l was obtained from condensation reaction 1l and 2 as a red solid; m.p.: 248–250 °C; Yield: 83%; 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.07–7.05 (d, J = 7.8 Hz, 2H), 6.55–6.53 (d, J = 7.8 Hz, 2H), 4.66 (s, 1H), 2.46 (s, 4H), 2.26–2.16 (q, J = 16.4 Hz, 4H), 1.08 (s, 6H), 0.99 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 197.30 (C=O), 162.45 (C=C-O), 154.70 (Ar-C), 135.47 (Ar-C), 129.29 (Ar-C), 115.85 (Ar-C), 115.23 (Ar-C), 50.72 (CH2), 40.81 (CH2), 32.23 (CH2), 30.93 (CH2), 29.11 (CH3) and 27.35 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H27O4 [M+H]+, 367.0652: found: 367.0673.

2.2.12. 9-Cyclohexyl-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (3m)

Compound 3m was obtained from condensation reaction 1m and 2 as a white solid; m.p.: 176–178 °C; Yield: 82%; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 2H), 5.46 (s, 1H), 3.31 (s, 2H), 2.50 (s, 4H), 2.23 (s, 4H), 1.22 (s, 1H), 1.06–0.85 (d, J = 18.0 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 193.30 (C=O), 165.54(C=C-O), 111.77 (Ar-C), 50.43 (CH), 40.71 (CH2), 34.51 (CH2), 33.01 (CH2), 31.25 (CH2), 29.20 (CH2), 27.42 (CH2), 25.93 (CH2), 24.52 (Cy-C), 23.21 (Cy-C), 23.15 (CH3) and 23.07 (CH3); High-resolution mass spectroscopy (HRMS) (ESI-qTOF): Calcd for C23H33O3 [M+H]+, 357.1081: found: 357.1064.

3. Results and Discussion

3.1. Chemistry

We studied the model reaction using benzaldehyde (1a) (1 mmol), and dimedone (2) (1 mmol) for the optimization of the reaction solvents, catalysts, temperatures, and observation of this study is described in Scheme 1 and Table 1.
Initially, we observed that the titled product was not perceived when the model reaction was carried out in the absence of a catalyst (Table 1, Entry 1). In the next step, we tested the reaction using different choline chloride-derived DESs as a reaction medium at 70 °C, which resulted in the desired product 3a in lower yields, and the results are given in (Table 1, Entry 2–10). In the presence of ChCl: Gly, this results in the formation of compound 3a in a good yield of 93% at 80 °C for 45 min. It was observed that ChCl: Gly (1:2) was a pre-eminent catalyst for this conversion. According to these results, the catalyst plays an important role in this transformation. We studied several DES catalysts. Among them, ChCl: Gly was highly active due to its relatively low viscosity and high thermal stability [46]. The remaining DESs showed lower activity because of direct interactions of the reactants with DESs, variation in acidity, and the physical properties of DESs. Due to these main reasons, the smooth interaction between reactants was not possible. The ChCl: Gly DES exhibited self-association of glycerol and choline chloride through the interaction of hydrogen bonding, which is the main reason for its high catalytic efficiency.
In the next step, we also screened the effect of temperature on the model reaction. The model reaction was stirred at a different temperature ranges from 70 to 90 °C, with an increment of 10 °C each time. The results exhibited that an increase in the temperature of the model reaction increased the product of the reaction. All these observations suggest that 80 °C is an optimum temperature in terms of reaction time and yield (Table 1, Entries 11, 13–14).
When the reaction was performed with the help of the glycerol, results in a 62% yield of the titled product as shown in (Table 1, Entry 15). Whereas when the model reaction was performed using the ChCl, results decrease in the yield of titles compound 3a at 80 °C was shown in (Table 1, Entry 16). This result proves that the excellent yield of the final product is due to the ChCl: Gly (1:2) and not to its individual components, glycerol and choline chloride. This is because of extensive hydrogen bonding between glycerol and quaternary ammonium salt choline chloride (Scheme 2) [46].
Furthermore, we also investigated the catalyst loading on the model reactions. The model reaction was carried out at different catalyst concentrations of 0.5, 1.0, 1.5, 2.0, and 2.5 g of ChCl: Gly (1:2) at 80 °C. Better results were observed when the model reaction was carried out using 2.0 g of ChCl: Gly (1:2) to give 93% yields of the titled product (Table 2, Entry 4).
The recycling and reuse of ChCl: Gly is the main advantage of our planned method. We studied the reusability of the ChCl: Gly. The reaction was carried out using aldehyde and dimedone under the optimized reaction parameters.
After the finishing point of the reaction, the reaction mass was poured on ice-cold water and product was extracted with EtOAc (2 × 20 mL) and an organic layer was washed with 5% NaHCO3 then dried over anhydrous NaSO4. In this reaction, ChCl: Gly (1:2) was recovered by simply evaporating water from the reaction mass. The recyclability of the catalytic efficiency of ChCl: Gly was tested for five consecutive cycles. There was no significant decrease in the yield observed as shown in Figure 1 (Table 3).
ChCl: Gly (1:2) exhibited prominent catalytic activity with extra thermal stability. Zhao S. H. et al. and Gary A. Baker described the thermal strength of ChCl: Gly at 150 °C [47]. We also confirmed this thermo-gravimetric analysis in a nitrogen atmosphere at 250 °C min−1 (Figure 2). This study suggests that the ChCl: Gly is stable up to 150 °C. In the next step, ChCl: Gly is heated at 100 °C for 300 min, resulting in no weight loss being observed. According to these results, our synthesized ChCl: Gly is stable below 100 °C.
We studied the stability of ChCl: Gly during recyclability of 3a with the help of IR of the recovered ChCl: Gly. The Fourier-transform infrared spectroscopy (FTIR) spectrum of pure ChCl: Gly showed peaks at 1040, 1482, and 2950 cm−1 and a broad peak at around 3324 cm−1. There was no considerable change in the Fourier-transform infrared spectroscopy (FTIR) spectra of pure ChCl: Gly and the IR spectra of ChCl: Gly recovered after the fifth cycle (Figure 3).
We undertook a comparative study of the ChCl: Gly with other previously reported catalysts for the synthesis of xanthene analogues. The comparison results proved that ChCl: Gly is the better catalyst in terms of its excellent yield and reusability with less reaction time (Table 4, Entry 10). In conclusion, ChCl: Gly is an efficient and greener approach for the synthesis of xanthene analogues.
Compound 3a was confirmed by 1H NMR and 13C NMR analysis. In 1H NMR spectra of the compound, 3a shows two distinct singlets at δ 1.21 and 1.24 ppm for the two methyl groups. Peaks were observed at δ 2.49 and 2.30 ppm for the -CH2-C=O and CH2 protons, respectively. These two signals confirmed that a dimedone ring is present in our synthesized compound. The peak observed at δ 5.56 ppm is due to the presence of -CH proton in compound 3a. In the 13C NMR spectrum of compound 3a, the peak at δ 195.65 ppm shows the presence of a -C=O group. The methine, methylene, and methane peaks observed at δ 50.43, 42.23, 32.45, 31.34, 29.56, and 29.33 ppm suggest the formation of the final compound 3a.
In conclusion, the effectiveness and better reaction time for the model reaction was observed at 80 °C by using 2 g of ChCl: Gly as a catalyst. With excellent reaction conditions in hand, the adaptableness of this approach was employing the synthesis xanthene analogues (3a–l). Various substituents on aryl aldehyde, including methoxy, methyl, nitro, halogen (-Cl,-Br, -I), and hydroxyl groups, were used. The synthesis of the compounds (3b–l) using the optimized reactions conditions and results are shown in Scheme 3. The result clearly suggests that the condensation reactions using ChCl: Gly catalyst show an excellent and remarkable performance irrespective of the electron-withdrawing/-donating groups present on the aryl aldehydes (Table 2), hence this method is facile, efficient, and general for the synthesis of xanthene analogues. All the synthesized final compounds (3a–l) were well characterized by 1H NMR and 13C NMR spectroscopic techniques and are incorporated in the Supplementary Material.
The reaction mechanism cycle for the preparation of xanthene analogues employing ChCl: Gly is the catalyst. In the first step, benzaldehyde activated by ChCl: Gly results in the formation of intermediate I. In the next step, ChCl: Gly reacts with dimedone to give the enol product II. In the third step, intermediate I reacts with II to afford the addition of the product III. Further formation of the alkylation product V occurs due to the reaction of II and III via removal of the H2O molecule. In the next step, intramolecular cyclization of V occurs to give VI. In the last step, elimination of the H2O molecule using ChCl: Gly results in the formation of the titled xanthene analogues 3a and regeneration of the catalyst. The detailed reaction mechanism is presented in Scheme 4.

3.2. Biological Activity

3.2.1. Antitubercular Activity Screening

The synthesized xanthene derivatives (3a–m) were screened for their in vitro antitubercular activity against MTB H37Ra American Type Culture Collection 25177 (ATCC 25177) and M. bovis BCG (ATCC 35743) strain in liquid medium [56]. We developed the well-known (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) (XTT) reduction menadione assay (XRMA) of an antitubercular screening protocol (incorporated in the Supplementary Material) using a standard reference, i.e., rifampicin drug, and the minimum inhibitory concentration (MIC) and inhibitory concentration (IC50) values are presented in Table 5.
Among all the synthesized xanthene derivatives compounds, 3d, 3e, 3f, 3j, and 3k were found to have prominent antimycobacterial activity against the MTB H37Ra and M. bovis BCG strain with MIC values of 2.5–15.10 and 0.26–14.92 µg/mL, respectively. However, the rest of the xanthene derivatives 3a, 3b, 3c, 3g, 3h, 3i, 3k, and 3l were inactive against the MTB H37Ra and M. bovis BCG strain with MIC ≥ 30 µg/mL.

3.2.2. Structure–Activity Relationship (SAR)

According to the activity data, the xanthene analogues showed excellent antitubercular activity and the results are presented in Table 5. The biological activity results revealed that the activity was significantly impacted by various substituents present on the aryl ring.
Firstly, we will elaborate the antitubercular activity of xanthene analogues against the MTB H37Ra strain. From the xanthene analogues series (3a–m), compound 3a, without any substitution on the aryl ring, displayed lesser potency against the MTB H37Ra strain with an MIC value >30 µg/mL as compared to the standard drug rifampicin and the results are displayed in Table 5. Compounds 3b (R2 = -methyl) and 3c (R3 = -methyl) showed lower antitubercular activity against the MTB H37Ra strain with MIC ≥ 30 µg/mL. When the -methoxy group was introduced in compound 3d (R2 = -methoxy), it showed excellent activity against the MTB H37Ra strain with MIC = 15.10 μg/mL. When a -methoxy group was present in the aryl ring at the para position as in compound 3e (R3 = -methoxy), it showed excellent activity against the MTB H37Ra strain with an MIC value of 4.20 µg/mL with reference to the standard drug. When a -methoxy group was introduced at both R2 and R3 in compound 3f, it exhibited prominent antimycobacterial activity against the MTB H37Ra strain with MIC = 2.25 μg/mL.
When a nitro group was introduced in compound 3g (R2 = -NO2), it exhibited less activity against the MTB H37Ra strain with MIC ≥ 30 µg/mL with reference to the standard drug. Replacing the nitro group with an iodo group in compound 3h (R2 = -I) resulted in inactivity against the MTB H37Ra strain with MIC ≥ 30 µg/mL. Installation of a bromo group at the para position of the aryl group in 3i (R3 = -Br) resulted in inactivity against the MTB H37Ra strain with MIC ≥ 30 µg/mL. Replacing a bromo by a chloro group at the para position in compound 3j (R3 = -Cl) resulted in the compound being highly potent against the MTB H37Ra strain with MIC = 4.74 µg/mL. When the position of the chloro group was changed in 3k (R2 = -Cl), it showed moderate antitubercular activity against the MTB H37Ra strain with MIC = 8.34 µg/mL as compared to compound 3j. When a hydroxy group was present at the para position in compound 3l (R3 = -OH), it was inactive against the MTB H37Ra strain with MIC ≥ 30 µg/mL. In compound 3m, when the aryl ring was replaced by a cyclohexane ring, it was found to be inactive against the MTB H37Ra strain with MIC ≥ 30 µg/mL. Hence, among all the synthesized xanthene derivatives 3a–m, compounds 3d, 3e, 3f, 3j, and 3k were found to be highly potent against the MTB H37Ra strain and the details are disclosed in Table 5.
Further, all the compounds were also tested for antitubercular activity against the M. bovis BCG strain. From the series (3a–m), compound 3a, without any substituent present on the aryl ring, showed no activity against the M. bovis BCG strain with MIC ≥ 30 µg/mL and the results are presented in Table 5. Compounds 3b i (R2 = -Me) and 3c (R3 = -Me) were found to be inactive against the M. bovis BCG strain with MIC ≥ 30 µg/mL. When methoxy was introduced in compound 3d (R2 = -OMe), it presented prominent antitubercular activity against the M. bovis BCG strain MIC = 14.92 µg/mL. Introduction of a methoxy group at the para position of the aryl ring in compound 3e (R3 = -OMe) and 3f (R2 = R3 = -OMe) resulted in potency against the M. bovis BCG strain with MIC = 0.26 and 1.22 µg/mL, respectively. When a nitro group was present at the R2 position in compound 3g (R2 = -NO2), it was found to be inactive against the M. bovis BCG strain with MIC ≥ 30 µg/mL.
Replacing the nitro group by an iodo group in 3h (R2 = -I), the compound was found to be inactive towards the M. bovis BCG strain with MIC ≥ 30 µg/mL. Introduction of a bromo group at the para position of the aryl group in 3i (R3 = -Br) resulted in the compound being inactive against the M. bovis BCG strain with MIC ≥ 30 µg/mL. When the chloro group was present at the para position in 3j (R3 = -Cl), the compound was highly active against the M. bovis BCG strain with MIC = 2.58 µg/mL. When the position of the chloro group was changed in 3k (R2 = -Cl), it showed moderate antitubercular activity against the M. bovis BCG strain with MIC = 6.13 µg/mL as compared to compound 3j. Compound 3l (R3 = -OH) did not show antitubercular activity against the M. bovis BCG strain with MIC ≥ 30 µg/mL. In compound 3m, the aryl group was replaced by a cyclohexane ring and the antitubercular activity against the M. bovis BCG strain was decreased, with an MIC value >30 µg/mL. Hence, among all the xanthene derivatives (3a–m), compounds 3d, 3e, 3f, 3k, and 3l were highly potent against the M. bovis BCG strain and the results are presented in Table 5.

3.3. Cytotoxicity

Among the prepared xanthene analogues, the most active compounds 3d, 3e, 3f, 3j, and 3k were further evaluated for cytotoxicity against human cell lines, including MCF-7, A549, HCT 116, and THP-1, using the well-developed tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [57]. The toxicity results revealed that most of these xanthene analogues were nontoxic and showed specific activity against the MTB and M. bovis BCG strains, with GI50/GI90 (>100 µg/mL) (Table 6).

3.4. Selectivity Index (SI)

SI determines the most active compounds selective towards mycobacteria but remain nontoxic against host human cancer cell lines. The drug susceptibility study indicates that when the SI was >10, then these compounds were more selective as antitubercular agents. Therefore, the most active compounds 3e (SI = 20), 3f (SI = 44), 3j (SI = 18), and 3k (SI = 14) exhibited >10 SI, revealing that these xanthene analogues act as excellent antitubercular agents. The detailed study is summarized in Table 7.

3.5. Antibacterial Activity

The specificity of the most active xanthene analogues 3d, 3e, 3f, 3j, and 3k was estimated for their antibacterial activity against the Gram-negative bacteria Escherichia coli and Pseudomonas fluorescence and the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. According to the antibacterial activity data, the most potent compounds were inactive towards the tested bacterial strains. This activity results show that the most potent compounds were highly specific against the MTB H37Ra and M. bovis BCG strains and the detailed study is described in Table 8.

3.6. ADME Properties

The success of a drug is determined not only by good efficacy but also by an acceptable ADME (absorption, distribution, metabolism, and excretion) profile. In this study, we calculated the molecular volume (MV), molecular weight (MW), logarithm of the partition coefficient (miLogP), number of hydrogen bond acceptors (n-ON), number of hydrogen bond donors (n-OHNH), topological polar surface area (TPSA), number of rotatable bonds (n-ROTB), and Lipinski’s rule of five [58] using the Molinspiration online property calculation toolkit [59]. Absorption (% ABS) was calculated by: % ABS = 109 − (0.345 × TPSA) [60].
The drug-likeness model score (a collective property of the physicochemical properties, pharmacokinetics, and pharmacodynamics of a compound represented by a numerical value) was computed by MolSoft software [61]. A computational study of all the synthesized compounds was performed for the prediction of ADME properties and the values obtained are presented in Table 9. It was observed that the compounds exhibited a good % ABS (% absorption), ranging from 69.11 to 85.02%.
Furthermore, the compounds 3j and 3k did not violate Lipinski’s rule of five (miLogP ≤ 5). A molecule that is likely to be developed as an orally active drug candidate should show no more than one violation of the following four criteria: miLogP (octanol-water partition coefficient) ≤ 5, molecular weight ≤ 500, number of hydrogen bond acceptors ≤ 10, and number of hydrogen bond donors ≤ 5 [62]. The larger the value of the drug-likeness model score, the higher the probability that the particular molecule will be active. All the tested compounds followed the criteria for orally active drugs and therefore, these compounds may have good potential for eventual development as oral agents.

4. Conclusions

In conclusion, a facile and environmentally benign approach was developed for the synthesis of xanthene analogues using a recyclable and inexpensive ChCl: Gly catalytic solvent-free system. This reaction protocol revealed several advantages, including high atom efficiency, mild reaction conditions, uniqueness, easy workup procedure, clean reaction profiles, and eco friendliness. Additionally, all the prepared xanthene analogues were screened for their in vitro antitubercular activity against the MTB H37Ra and M. bovis BCG strains. Among all the screened compounds, 3d, 3e, 3f, 3j, and 3k were found to be highly active compounds, with MIC values in the range of 2.5−15.10 µg/mL against the M. bovis BCG strain and 0.26–14.92 µg/mL against the MTB H37Ra strain, respectively. The most active compounds were found to be nontoxic against MCF-7, A549, HCT 116, and THP-1 cancer cell lines by employing the MTT method. Highly potent xanthene derivatives 3d, 3e, 3f, 3j, and 3k were found to have a selectivity index of >10 against MCF-7, A549, HCT 116, and THP-1, which suggests that they can act as promising antitubercular agents. All these results confirm that compounds 3d, 3e, 3f, 3j, and 3k can be further modified as lead drug molecules.

Supplementary Materials

The following are available online. Biological activity protocol and supplementary data (copies of 1H and 13C NMR spectra of all the synthesized compounds).

Author Contributions

M.A.B. and H.M.A.-T. conceived and designed the experiments; M.A.B. and S.A.A. performed chemical synthesis and purifications; A.M.N. and A.A.-D. performed biological assays (tubercular activity against MTB and M. bovis BCG strains); M.A.B. wrote the paper; S.A.A. helped in the revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research through Research Group no: (RG—1435-006).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Biological activity protocol and supplementary data (copies of 1H and 13C NMR spectra of all the synthesized compounds) associated with this article can be found through the “Supplemental Content” section of this article’s webpage.

Acknowledgments

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research through Research Group no: (RG—1435-006).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from authors.

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Molecules 26 03667 g001 550
Figure 1. Xanthene-incorporated bioactive molecules.
Figure 1. Xanthene-incorporated bioactive molecules.
Molecules 26 03667 g001
Molecules 26 03667 sch001 550
Scheme 1. Model reaction.
Scheme 1. Model reaction.
Molecules 26 03667 sch001
Molecules 26 03667 sch002 550
Scheme 2. Hydrogen bonding between glycerol and choline chloride.
Scheme 2. Hydrogen bonding between glycerol and choline chloride.
Molecules 26 03667 sch002
Molecules 26 03667 g002 550
Figure 2. Thermo-gravimetric analysis of ChCl: Gly (DES).
Figure 2. Thermo-gravimetric analysis of ChCl: Gly (DES).
Molecules 26 03667 g002
Molecules 26 03667 g003 550
Figure 3. FTIR spectra of (a) ChCl: Gly measured before reaction (b) ChCl: Gly measured after fifth cycle during recyclability of reaction (c) ChCl: Gly measured after 300 min at 100 °C.
Figure 3. FTIR spectra of (a) ChCl: Gly measured before reaction (b) ChCl: Gly measured after fifth cycle during recyclability of reaction (c) ChCl: Gly measured after 300 min at 100 °C.
Molecules 26 03667 g003
Molecules 26 03667 sch003a 550Molecules 26 03667 sch003b 550
Scheme 3. Synthesis of xanthene derivatives (3a–l) by using ChCl: Gly as a catalyst. a Reaction conditions: aldehydes (1a–m) (1 mmol) and dimedone (2) (1 mmol) in ChCl: Gly (2.0 g) stirred at 45 °C; b isolated yields, cmelting points are in good agreements with previously reported compounds in the literature [50].
Scheme 3. Synthesis of xanthene derivatives (3a–l) by using ChCl: Gly as a catalyst. a Reaction conditions: aldehydes (1a–m) (1 mmol) and dimedone (2) (1 mmol) in ChCl: Gly (2.0 g) stirred at 45 °C; b isolated yields, cmelting points are in good agreements with previously reported compounds in the literature [50].
Molecules 26 03667 sch003aMolecules 26 03667 sch003b
Molecules 26 03667 sch004 550
Scheme 4. Reaction mechanism cycle for the preparation of compounds 3a.
Scheme 4. Reaction mechanism cycle for the preparation of compounds 3a.
Molecules 26 03667 sch004
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
EntrySolventTemperature (°C)Time (min)Yield (%) b
1-70520-
2ChCl:Urea(1:2)708060
3ChCl:Thiourea(1:2)708058
5ChCl:Adipic Acid (1:1)708028
4ChCl:Oxalic Acid(1:1)708063
7ChCl:Malonic Acid(1:1)708038
6ChCl:Succinic Acid(1:1)708046
9ChCl:ZnCl2 (1:2)708530
8ChCl:FeCl3 (1:2)708535
10ChCl:Gly (1:1)708076
11ChCl:Gly (1:2)706082
12ChCl:Gly (1:3)706083
13ChCl:Gly (1:2)804593
14ChCl:Gly (1:2)904593
15Gly808062
16ChCl8052025
a Reaction conditions: benzaldehyde 1 (1 mmol), dimedone 2 (1 mmol and DES (2.0 g); b Isolated yields. ChCl: Choline Chloride; Gly: Glycerol.
Table
Table 2. Optimization of deep eutectic solvent a.
Table 2. Optimization of deep eutectic solvent a.
EntryChCl: Gly (g)Time (min)Temp (°C)% Yield b
10.5458028
21458058
31.5458078
42458093
52.5458094
a Reaction conditions: benzaldehyde 1 (1 mmol), dimedone 2 (1 mmol) and ChCl: Gly (2.0 g); b Isolated yields.
Table
Table 3. Recycling of ChCl: Gly (DES) for the synthesis of compound 3a a.
Table 3. Recycling of ChCl: Gly (DES) for the synthesis of compound 3a a.
EntryRunTime (min)% Yield b
1Fresh4593
214593
324591
434589
544585
654582
a Reaction conditions: benzaldehyde 1 (1 mmol), dimedone 2 (1 mmol) and ChCl: Gly (2.0 g); b Isolated yields.
Table
Table 4. Comparative catalytic study of ChCl: Gly with the reported catalysts.
Table 4. Comparative catalytic study of ChCl: Gly with the reported catalysts.
EntryCatalystAmount of CatalystTime (min)Yield (%)Solvent/ConditionRef.
1β-CD (1 mmol)1 mmol10 h96EtOH/60 °C[48]
2SBSSA30 mg10 h98EtOH/reflux[49]
3FeCl3.6H2O (10 mol%)10 mol%6 h92[bmim][BF4]/80 °C[50]
4Amberlyst-15200 mg5 h92CH3CN/Reflux[51]
5Cellulose sulfonic acid50 mg5 h94Solvent free/110 °C[52]
6[bmim][HSO4] (42 mol%)42 mol%3 h85Solvent free/100 °C[40]
7Fe3+ montmorillonite85 mg6 h94EtOH/reflux[53]
8Zr(DP)210 mol %24 h98EtOH/80 °C[54]
9ZnO-CH3COCl30 mol %5 h86CH3CN/reflux[55]
10ChCl:Gly2.0 g45 min93ChCl:Gly act as a solventPresent work
Table
Table 5. In vitro antimycobacterial activity of xanthene conjugates in (µg/mL).
Table 5. In vitro antimycobacterial activity of xanthene conjugates in (µg/mL).
CompoundMTB H37RaM. bovis BCG
a MICa IC50a MICa IC50
3a>30>30>30>30
3b>30>30>30>30
3c>30>30>30>30
3d15.103.2014.923.40
3e4.200.740.260.28
3f2.50.791.220.32
3g>30>30>30>30
3h>30>30>30>30
3i>30>30>30>30
3j4.740.502.580.6
3k7.82.39.45.8
3l>30>30>30>30
3m>30>30>30>30
bRifampicin0.0450.00170.0170.0015
a MIC/IC50 in mg/mL. Antitubercular activity of all compounds was investigated using serial dose-dependent dilutions protocol. b Rifampicin as a standard drug acts as a positive control.
Table
Table 6. In vitro cytotoxicity of active xanthene analogues (GI50 in μg/mL).
Table 6. In vitro cytotoxicity of active xanthene analogues (GI50 in μg/mL).
CompoundMCF-7A549HCT 116THP-1
3d>100>100>100>100
3e>100>100>100>100
3f>100>100>100>100
3j>100>100>100>100
3k>100>100>100>100
Rifampicin>100>100>100>100
Paclitaxel0.00480.00350.02600.1374
GI50 indicates the concentration that inhibits 50% of the growth of cells.
Table
Table 7. Selectivity index against dormant MTB H37Ra and M. bovis BCG.
Table 7. Selectivity index against dormant MTB H37Ra and M. bovis BCG.
CompoundMCF-7A549HCT 116THP-1
MTBBCGMTBBCGMTBBCGMTBBCG
3d77777777
3e20330203332033020330
3f4482428242824482
3j1840184018401840
3k1412141214121412
Rifampicin196222196222196222196222
Table
Table 8. Antibacterial activity of compounds MIC (μg/mL).
Table 8. Antibacterial activity of compounds MIC (μg/mL).
CompoundE. coliP. fluorescensS. aureusB. subtilis
3d>30>30>30>30
3e>30>30>30>30
3f>30>30>30>30
3j>30>30>30>30
3k>30>30>30>30
Kanamycin3.34 ± 0.411.01 ± 0.09>61.922.78 ± 0.85
Ampicillin4.17 ± 1.0412.47 ± 1.282.86 ± 0.7829.53 ± 1.88
Table
Table 9. Pharmacokinetic parameters important for good oral bioavailability and its drug likeness model score.
Table 9. Pharmacokinetic parameters important for good oral bioavailability and its drug likeness model score.
Com% ABSTPSA (A2)n-ROTBMVMWmiLogPn-ONn-OHNHLipinski ViolationDrug Likeness Model Score
Rule----<500≤5<10<5≤1
3a94.0343.381336.59350.465.20301−1.31
3b94.0343.381353.15364.495.62301−0.98
3c94.0343.382353.15364.495.65301−1.27
3d90.8452.612362.13380.485.23402−0.89
3e90.8452.613362.13380.485.25402−1.09
3f87.6661.842387.8410.514.845030.41
3g78.2289.201359.92395.455.13601−0.85
3h94.0343.381360.58476.356.26301−0.87
3i94.0343.381354.48429.356.01301−1.16
3j94.0343.381350.12384.905.88301−0.77
3k87.0563.601344.61366.464.72401−0.72
3l94.0343.381355.18356.515.79311−1.32
Com: Compound, % ABS: percentage absorption, TPSA: topological polar surface area, n-ROTB: number of rotatable bonds, MV: molecular volume, MW: molecular weight, milogP: logarithm of partition coefficient of the compound between n-octanol and water, n-ON acceptors: number of hydrogen bond acceptors, n-OHNH donors: number of hydrogen bonds donors.
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Bhat, M.A.; Naglah, A.M.; Akber Ansari, S.; Al-Tuwajiria, H.M.; Al-Dhfyan, A. ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity. Molecules 2021, 26, 3667. https://doi.org/10.3390/molecules26123667

AMA Style

Bhat MA, Naglah AM, Akber Ansari S, Al-Tuwajiria HM, Al-Dhfyan A. ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity. Molecules. 2021; 26(12):3667. https://doi.org/10.3390/molecules26123667

Chicago/Turabian Style

Bhat, Mashooq A., Ahmed M. Naglah, Siddique Akber Ansari, Hanaa M. Al-Tuwajiria, and Abdullah Al-Dhfyan. 2021. "ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity" Molecules 26, no. 12: 3667. https://doi.org/10.3390/molecules26123667

APA Style

Bhat, M. A., Naglah, A. M., Akber Ansari, S., Al-Tuwajiria, H. M., & Al-Dhfyan, A. (2021). ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity. Molecules, 26(12), 3667. https://doi.org/10.3390/molecules26123667

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