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Article

Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety

by
Van Hien Pham
1,
Thi Phuong Dung Phan
2,
Dinh Chau Phan
3,* and
Binh Duong Vu
1,*
1
Drug R&D Center, Vietnam Military Medical University. No.160, Phung Hung str., Phuc La ward, Ha Dong district, Hanoi 100000, Vietnam
2
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy. No. 15, Le Thanh Tong Str., Hoan Kiem district, Hanoi 100000, Vietnam
3
Hanoi University of Science and Technology. No.1, Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district, Hanoi 100000, Vietnam
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(21), 4000; https://doi.org/10.3390/molecules24214000
Submission received: 3 October 2019 / Revised: 29 October 2019 / Accepted: 4 November 2019 / Published: 5 November 2019
Browse Figure
Review Reports Versions Notes

Abstract

:
Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl moiety. The new synthesized compounds were tested for activities against some Gram-negative and Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds 4e and 5e possessed cytotoxicity against tested human cancer cell lines.

1. Introduction

The hydrazide-hydrazones derivatives, which play an important role in organic and medicine chemistry, have attracted a large number of researchers over the years because of their promising biological activities, including antimicrobial [1,2,3,4], anticancer [5,6,7], antituberculosis [2,8,9,10], antiviral [11], and anticonvulsant [2] activities. Some hydrazide-hydrazone components have been considered as drugs and have been used in clinics, such as nitrofurazone, furazolidone, nitrofurantoin.
Adamantane derivatives are important constituents in medicinal chemistry due to their multiple bioactivities. In the 1960s, the first adamantane derivative, amantadine, was found to have antiviral [12,13,14] activity. A number of studies were conducted, focusing on such derivatives with the hope to find new compounds and biological activities. As a result, many adamantane derivatives were discovered with numerous biological activities, such as antiviral [15,16,17,18,19,20], antimicrobial [18,20,21,22,23,24,25,26,27,28,29,30], anticancer [23,27,31,32,33,34,35], angiogenesis inhibition [36], anti-inflammation [37], 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition [38,39,40], and tyrosinase inhibition [41] activities. Among them, nine compounds were approved for use in clinics, including amantadine, memantine, rimantadine, tromantadine, adapalene, vildagliptine, saxagliptine, bromanatane, and adapromine. Therefore, the combination of two moieties, hydrazone and adamantane, had potential to confer new molecules with promising biological activities. In this study, we report the synthesis and biological activities of hydrazide-hydrazones with the 1-adamantyl carbonyl moiety.

2. Results and Discussion

2.1. Chemistry

In this study, adamantane-1-carbohydrazide was used as the key intermediate. It was initially prepared by esterification of 1-adamantane carboxylic acid (1) and methanol under catalysis of 98% H2SO4 to yield methyl ester 2. Then, ester 2 was reacted with hydrazine hydrate to yield adamantyl-1-carbohydrazide (3). Subsequently, compound 3 was condensed with aromatic aldehydes and ketones to yield the corresponding hydrazide-hydrazones 4a–i and 5a–k, as seen in Scheme 1 and Table 1. The structure of hydrazide hydrazones 4a–i and 5a–k was confirmed by 1H-NMR, 13C-NMR, and electron impact (ESI-MS) mass spectral data.

2.2. In Vitro Antimicrobial Activity

The newly synthesized hydrazide-hydrazones 4a–i and 5a–k were tested for their in vitro growth inhibition against standard strains of the National Institute for Food Control (NIFC, Vietnam), including three Gram-negative bacteria, including Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), and Salmonella enterica (ATCC12228); three Gram-positive bacteria, including Enterococcus faecalis (ATCC13124), Staphylococcus aureus (ATCC25923), and Bacillus cereus (ATCC 13245); and one yeast-like pathogenic fungus, Candida albicans (ATCC10231). The primary screening was conducted using the microplate dilution method, which utilized Luria-Bertani (LB) broth medium. The antibiotic Streptomycin and antifungal drug Cyloheximide were used as the positive samples. The results of preliminary antimicrobial testing of the newly synthesized hydrazide-hydrazones 4a–i and 5a–k are presented in Table 2 and Table 3.
The results of antimicrobial testing showed that all newly synthesized hydrazide-hydrazones possessed various inhibition effects on the tested Gram-positive bacteria and yeast-like fungus from moderate to serious activities. Strong antibacterial activity was found for compounds 4a, 4d, 5a, and 5c. Meanwhile, compound 4a strongly inhibited EF, SA, BC, and CA, with an MIC of 12.5 μM (for the four strains) and IC50 values of 6.35 μM, 6.77 μM, 6.12 μM, and 6.37 μM, respectively. Additionally, compounds 4d, 5a, and 5c have good inhibitory effects on EF and CA, with MICs of 12.5 μM and 6.26 μM, 12.5 μM and 12.5 μM, 12.5 μM and 12.5 μM; and IC50 values of 6.88 μM and 3.56 μM, 6.73 μM and 6.25 μM, and 6.77 μM and 6.66 μM, respectively. Moreover, compounds 4f and 4h showed good results in inhibition of the yeast-like fungus CA with MICs of 12.5 μM (for both synthesized compounds) and IC50 values of 6.77 μM and 6.45 μM, respectively. Other synthesized compounds showed moderate inhibition of the tested Gram-positive bacteria and C. albicans.
Regarding the structure–antimicrobial activity relationship of the synthesized compounds, inhibition increased significantly for compounds possessing an –OH (para) group on the benzyl ring (compounds 4a and 5a). Within the hydrazide-hydrazones 4a–i, it was suggested that the inhibition against EF did not change substantially when having –NO2, –OC2H5, or an –OCH3 group at position 4 of the benzyl ring, but decreased if they were replaced by a –Br group. Otherwise, the presence of only one substituent on the benzyl ring inhibited SA better than that of two substituents. In the inhibition against BC, it seemed that the presence of 4-OH, 4-NO2, 4-OC2H5 enhanced the activity; however, it was reduced when the substituent was a 4-OCH3 group. In addition, the inhibition of CA showed a good result while having only one substituent of 4-NO2, 4-OC2H5, or 4-OCH3 on the benzyl ring.
In hydrazide-hydrazones 5a–k, it seemed that the presence of the benzyl ring enhanced the antimicrobial activity. Compound 5k, containing two methyl groups (2-CH3 and 5-CH3), showed good inhibition against Gram-positive bacteria and the yeast-like fungus C. albicans. The replacement of 2-CH3 by 2-OH enhanced the activity, particularly against C. albicans, but made no improvement to the inhibition of Gram-positive bacteria.

2.3. In Vitro Cytotoxicity

All the synthesized hydrazide-hydrazones 4a–i and 5a–k were evaluated for their cytotoxicity in four human cancer cell lines, including hepatic cancer cell line Hep3B, human cervical cancer cell line HeLa, human lung cancer cell line A549, and human breast carcinoma MCF-7, in line with a previous publication [42]. As shown in Table 4, some of the synthesized hydrazide-hydrazones exhibited antiproliferative activity against the tested cancer cell lines. Among them, compound 5e demonstrated the most potent cytotoxicity on cell viability of 37.78 ± 2.44%, 40.42 ± 0.38%, 19.62 ± 1.74%, and 34.13 ± 2.22% in HeP3B, Hela, A549, and MCF-7 cell lines, respectively, at a concentration of 100 μM. In addition, compound 4e inhibited Hela, A549, and MCF-7 cells, with cell viabilities of 44.37 ± 1.39%, 38.51 ± 1.59%, and 38.69 ± 1.20% at a concentration of 100 μM, respectively. Other compounds showed slight cytotoxicity on the tested cancer cell lines. Structure–cytotoxicity relationship analysis revealed that compounds 4e and 5e, containing both 3-NO2 and 4-Cl groups on the benzyl ring, have significant cytotoxicity against the four tested cancer cell lines.

3. Experimental

3.1. General

Melting point (°C) was measured in a glass microtube using a MP50 Mettler Teledo electrothermal melting point apparatus. NMR spectra were obtained with a Bruker Biospin AVANCE III spectrometer system monitoring at 500 MHz in DMSO-d6; the chemical shifts (δ, ppm) were expressed and coupling constants (J) were given in Hz using tetramethylsilane as the internal standard. Mass spectra (MS) were recorded on an Agilent 910-TQ-FT-MS system. Monitoring the reactions and preliminary purity checking of synthesized compounds were conducted by thin layer chromatography (TLC) using precoated aluminum sheet 60 F254 plates (Merck KGaA Co., Darmstadt, Germany; EMD Milipore Corp., MA, USA) and visualization with UV at 254 nm. The bacterial and fungus strains were supplied by National Institute for Food Control (NIFC, Hanoi, Vietnam) including Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella enterica (ATCC12228), Enterococcus faecalis (ATCC13124), Stapphylococus aureus (ATCC25923), Bacillus cereus (ATCC 13245), and Candida albicans (ATCC10231). This study was conducted on cancer cell lines supplied by Advanced Center for Bioorganic Chemistry (ACBC) of the Institute of Marine Biochemistry (IMBC), Vietnam Academy Science and Technology (VAST), i.e., hepatic cancer cell line Hep3B, human cervical cancer cell line HeLa, human lung cancer cell line A549, and human breast carcinoma MCF-7.

3.2. Synthesis of Methyl Adamantane-1-Carboxylate (2)

A mixture of 5 g (2.7 mmoL) adamantane-1-carboxylic acid, 50 mL methanol (1235 mmoL), and 9.2 g H2SO4 98% was stirred under reflux conditions. The reaction was monitored by TLC performed in n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) and visualized under UV at 254 nm. After the reaction, the mixture was adjusted to pH 7–8 with 10% NaHCO3 aqueous solution. Then, the mixture was stabilized to room temperature before 200 mL ice water was poured into it to cause precipitation. The separate precipitate was filtered, washed with water, dried, and crystallized to obtain 4.92 g of white, needle-shaped crystals with a yield of 98.4% [18].

3.3. Synthesis of Adamantane-1-Carbohydrazide (3)

A mixture of 4 g (20 mmoL) compound 2 and 25 mL (412 mmoL) 80% hydrazine hydrate aqueous solution were refluxed. The reaction was monitored by TLC using n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) as the mobile phase and visualized under UV at 254 nm. At completion, 200 mL of ice water was added to the mixture. The separate precipitate was filtered and washed with water, dried to obtain 3.82 g of opalescent scaly solid with a yield of 95.5% [18].

3.4. Synthesis of Hydrazide-Hydrazones 4a–i and 5a–k

A mixture of adamantane-1-carbohydrazide (3) and 1 mmoL of the appropriate aldehydes or ketones and 15 mL EtOH was stirred in reflux conditions. The reaction was monitored by TLC using the mobile phase as n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) and visualized under UV at 254 nm. At completion, the solvent was removed under vacuum to yield a viscous liquid. It was allowed to stand at 0–5 °C to crystallize. Then, the crystal was filtered, washed with cold ethanol, and dried to obtain hydrazide-hydrazones 4a–i and 5a–k.
N′-(1-(4-hydroxyphenyl)ethylidene)adamantane-1-carbohydrazide (4a): M.p.: 252.5–254.1 °C, Yield 30.6%. 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.74 (1H, s, NH-N); 9.44 (1H, s, OH); 7.64 (2H, dd, J1 = 2.0 Hz, J2 = 7.0 Hz; Ar-H); 6.78 (2H, m, Ar-H); 2.16 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.90 (6H, s, CH2 Ad); 1.70 (6H, s, Adamantane-H). 13C-NMR (500 MHz, DMSO-d6, δ ppm): 172.6 (1C, CO); 158.8 (1C, Ar-C); 156.5 (1C, C=N); 128.9 (1C, C1); 127.9 (2C, Ar-C); 115.0 (2C, Ar-C); 38.2 (3C, Adamantane-C); 36.0 (3C, Adamantane-C); 27.6 (3C, Adamantane-C); 14.0 (1C, CH3). ESI-MS (m/z): [M − 1]−1 = 311.0; [M + 1]+1 = 313.1.
N′-(1-(4-nitrophenyl)ethylidene)adamantane-1-carbohydrazide (4b): M.p.: 226.0–227.6 °C; Yield 60.5%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.72 (1H, s, NH-N); 8.26 (2H, dd, J1 = 2.0 Hz, J2 = 7.0 Hz, Ar-H); 8.05 (2H, dd, J1 = 2.0 Hz, J2 = 7.5 Hz, Ar-H); 2.32 (3H, s, CH3); 2.01 (3H, s, Adamantane-H); 1.95 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M − 1]−1 = 340,0; [M + 1]+1 = 342,0.
N′-(1-(4-ethoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4c): M.p.: 159.5–160.6 °C; Yield 32.2%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.47 (1H, s, NH-N); 7.74 (2H, d, J = 9.0 Hz, Ar-H); 6.95 (2H, d, J = 9,0 Hz, Ar-H); 4.06 (2H, dd, J1 = 7.0 Hz; J2 = 14.0 Hz, OCH2); 2.19 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.91 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); 1.33 (3H, t, J1 = 7.0 Hz, J2 = 14.0 Hz, CH3). ESI-MS (m/z): [M + 1]+1 = 341.0.
N′-(1-(3-nitro-4-methoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4d): M.p.: 182–184.1 °C; Yield 33.0%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.61 (1H, s, NH-N); 8.25 (1H, d, J = 2,5 Hz, Ar-H); 8.08 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.42 (1H, d, J = 7.0 Hz, Ar-H); 2.25 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.92 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 372.0; [M − 1]−1 = 370.0.
N′-(1-(3-nitro-4-chlorophenyl)ethylidene)adamantane-1-carbohydrazide (4e): M.p.: 188.2–189.3 °C; Yield 26.2%. 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.72 (1H, s, NH-N); 8.39 (1H, d, J = 2.0 Hz, Ar-H); 8.09 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.83 (1H, d, J = 8.5 Hz, Ar-H); 2.29 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.94 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H). ESI-MS (m/z): [M + 1]+1 = 375.9; [M − 1]−1 = 373.9.
N′-(1-(3-nitro-4-chlorophenyl)ethylidene)adamantane-1-carbohydrazide (4f): M.p.: 190.7–191 °C. Yield: 29.0%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.59 (1H, s, NH-N); 7.76 (2H, d, J = 8.5 Hz, Ar-H); 7.63 (2H, d, J = 8.5 Hz, Ar-H); 2.25 (3H, s, CH3); 2.02 (3H, s, Adamantane-H); 1.94 (6H, s, Adamantane-H); 1.72 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 374.9.
N′-(1-(4-methoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4g): M.p.: 171.6–173 °C; Yield 30.0%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.48 (1H, s, NH-N); 7.75 (2H, d, J = 8.5 Hz, Ar-H); 6.97 (2H, d, J = 9.0 Hz, Ar-H); 3.79 (3H, s, OCH3); 2.20 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.91 (6H, s, Adamantane-H); 1,70 (6H, s, Adamantane-H). ESI-MS (m/z): [M + 1]+1 = 327.0.
N′-(1-(4-methylphenyl)ethylidene)adamantane-1-carbohydrazide (4h): M.p.: 179.5–180.4 °C; Yield 37.3%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.48 (1H, s, NH-N); 7.75 (2H, d, J = 8.5 Hz, Ar-H); 6.97 (2H, d, J = 9.0 Hz, Ar-H); 3.79 (3H, s, OCH3); 2.20 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.91 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 311.0.
N′-(1-phenyl)ethylidene)adamantane-1-carbohydrazide (4i): M.p.: 174.4–175.2 °C; Yield 54.5%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 9.54 (1H, s, NH-N); 7.79 (2H, m, Ar-H); 7.43–7.41 (3H, m, Ar-H); 2.24 (3H, s, CH3); 2.01 (3H, s, Adamantane-H); 1.93 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H). ESI-MS (m/z): [M + 1]+1 = 297.0.
N′-(4-hydroxybenzylidene)adamantane-1-carbohydrazide (5a): M.p.: 289.6–290.5 °C; Yield 44.0%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 10.56 (1H, s, NH-C); 9.86 (1H, s, OH); 8.28 (1H, s, N=CH); 7.49 (2H, d, J = 8.5 Hz, Ar-H); 6.82 (2H, d, J = 8.5 Hz, Ar-H); 2.01 (3H, s, Adamantane-H); 1.87 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 298.9; [M − 1]−1 = 296.9.
N′-(4-ethoxybenzylidene)adamantane-1-carbohydrazide (5c): M.p.: 235.2–236.4 °C; Yield 15.1%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 10.61 (1H, s, NH-C); 8.32 (1H, s, N=CH); 7.57 (2H, d, J = 8.5 Hz, H2, H6); 6.97 (2H, d, J = 9.0 Hz, H3, H5); 4.07 (2H, m, OCH2); 2.00 (3H, s, CH Ad); 1.86 (6H, s, CH2 Ad); 1.70 (6H, s, CH2 Ad); 1.34 (3H, t, J1 = 7.0 Hz, J2 = 14.0 Hz, CH3); ESI-MS (m/z): [M + 1]+1 = 327.0.
N′-(3-nitro-4-chlorobenzylidene)adamantane-1-carbohydrazide (5e): M.p.: 247.8–248.5 °C; Yield: 50.6%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 11.12 (1H, s, NH-C); 8.43 (1H, s, N=CH); 8.29 (1H, d, J = 2.0 Hz, Ar-H); 7.96 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.82 (1H, d, J = 8.5 Hz, Ar-H); 2.01 (3H, s, Adamantane-H); 1.87 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 361.9; [M − 1]−1 = 359.9.
N′-(benzylidene)adamantane-1-carbohydrazide (5i): M.p.: 186.9–187.2 °C; Yield: 60.5%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 10.77 (1H, s, NH-C); 8.40 (1H, s, N=CH); 7.66–7.61 (2H, m, Ar-H); 7.45–7.40 (3H, m, Ar-H); 2.01 (3H, s, Adamantane-H); 1.88 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 283.0.
N′-(2-hydroxy-5-methylbenzylidene)adamantane-1-carbohydrazide (5j): M.p.: 247.6–248.8 °C; Yield 60.4%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 11.15 (1H, s, OH); 11.08 (1H, s, NH-C); 8.48 (1H, s, N=CH); 7.23 (1H, d, J = 1.5 Hz, Ar-H); 7.07 (1H, dd, J1 = 2.0 Hz, J2 = 8.0 Hz, Ar-H); 6.79 (1H, d, J = 8.5 Hz, Ar-H); 2.23 (3H, CH3); 2.01 (3H, s, Ar-H); 1.87 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 313.0; [M − 1]−1 = 310.9.
N′-(2,4-diemthylbenzylidene)adamantane-1-carbohydrazide (5k): M.p.: 283.5–284.0 °C; Yield 35.5%; 1H-NMR (500 MHz, DMSO-d6, δ ppm): 10.72 (1H, s, NH-C); 8.63 (1H, s, N=CH); 7.59 (1H, s, H6); 7.11 (2H, s, Ar-H); 2.36 (3H, s, CH3); 2.29 (3H, s, CH3); 2.02 (3H, s, Adamantane-H); 1.88 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 311.0.
Spectra of synthesized compounds were displayed in Supplemental Material file.

3.5. Dertemination of Antimicrobial Activity by the Dilution Method

The tested compounds 4a–i, 5a–k were dissolved in dimethylsulphoxide at the concentration of 100 mM, separately, to prepare the parent solutions. A total of 0.4 mL of the parent solution was withdrawn and 9.6 mL LB was added and mixed homogenously to obtain a working solution. Then, we prepared twofold serial dilution solutions in LB media at the concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56 μM, and 0.78 μM in 96 well plates, in triplicate. After that, 50 μL of microorganism suspension at 2 × 105 CFU/mL was inoculated to each well and incubated at 37 °C for 24 h. Streptomycin and cycloheximide were used as the positive samples. Minimum inhibitory concentration (MIC) was determined as the lowest concentration that completely inhibited the growth of the microorganism, which was detected by the naked eye. Half of the maximal inhibitory concentration (IC50) is defined as the concentration of tested compounds that inhibits 50% visual growth of the test microorganism, which was determined by turbidity measurement on a Bitotech microplate reader and using RawData software [43].

3.6. Determination of Cytotoxicity Activity

The MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide) method was conducted to determine the cytotoxicity of the synthesized compounds 4a–i, 5a–k on human cancer cell lines, including hepatic cancer cell line Hep3B, human cervical cancer cell line HeLa, human lung cancer cell line A549, and human breast carcinoma MCF-7, according to a previous publication [43]. The cells, which were seeded at 5 × 106 cell/well, were grown in 96-well plates with RPMI 1640 or DMEM media containing 10% fetal bovine serum (FBS), penicillin (100 IU/mL), and streptomycin (100 μg/mL) at 37 °C in a humid air incubator supplied with 5% CO2. The cells were allowed to grow for 24 h and then were removed to old media and treated with the sample. A total of 200 μL of the test samples was added to the well and incubated for 72 h in culture conditions. After removing the medium, 50 μL MTT solution (1 mg/mL in phosphate buffer saline) was then added to each well and the cells were further incubated at 37 °C for 4 h. After removing the MTT solution, 100 μL of isopropanol was added to each well. The absorbance was measured on a microplate reader (iMark™ Microplate Absorbance Reader, Bio-Rad Laboratories, CA, USA) at 570 nm. Suitable blank and positive controls (Camptothecine) were included. Cytotoxicity of the synthesized compounds was determined as the percent of cell survival, as follows: [OD (72 h)–OD (0 h)]/[OD(DMSO)–OD (0 h)]; where OD (72 h), OD (0 h), OD(DMSO) are the absorbance of test sample at 72 h, test sample at 0 h, and DMSO sample [42].

4. Conclusions

The synthesis and characterization of hydrazide-hydrazones with a 1-adamantane carbonyl moiety, 4a–i and 5a–k, were achieved. The synthesis was conducted by condensing adamantane-1-carbohydrazide (3) with substituted acetophenones to get compounds 4a–i, and with substituted benzaldehydes to get compounds 5a–k. The antimicrobial and cytotoxicity of the synthesized compounds were determined. The screening results revealed that compounds 4a, 4d, 5a, and 5c showed good antibacterial activity against Gram-positive bacteria and Candida albicans compared to known antibacterial and antifungal drugs. These compounds are considered as good candidates for new antimicrobial agents. Moreover, among the synthesized compounds, 4e and 5e displayed promising inhibitory activity against the growth of tested human cancer cell lines. Although the active compounds are considered to be good candidates as antimicrobial and antitumor agents, further studies, such as mechanism determination, should be undertaken.

Supplementary Materials

Supplementary materials can be found online.

Author Contributions

The manuscript was written by the contribution of all authors: Methodology, D.C.P.; Supervision, B.D.V.; Writing—original draft, V.H.P.; Writing—review & editing, T.P.D.P.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Molecules 24 04000 sch001 550
Scheme 1. Synthesis of hydrazide-hydrazones 4a–i and 5a–k.
Scheme 1. Synthesis of hydrazide-hydrazones 4a–i and 5a–k.
Molecules 24 04000 sch001
Table
Table 1. Melting point (m.p), yield (%), molecular formulae, molecular weight (Mol. Wt.) and Rf of hydrazide-hydrazones 4a–i and 5a–k.
Table 1. Melting point (m.p), yield (%), molecular formulae, molecular weight (Mol. Wt.) and Rf of hydrazide-hydrazones 4a–i and 5a–k.
Comp. No.R1R2m.p (°C)Yield (%)Molecular Formular (Mol. Wt.)TLC * (Rf)
4aH4-OH252.5–254.130.6C19H24N2O2 (312.41)0.36
4bH4-NO2226.0–227.660.5C19H23N3O3 (341.41)0.58
4cH4-OC2H5159.5–160.632.2C21H28N2O2 (340.47)0.57
4d3-NO24-OCH3182.0–184.133.0C20H25N3O4 (371.44)0.44
4e3-NO24-Cl188.2–189.326.2C19H22ClN3O3 (375.85)0.56
4fH4-Br190.7–191.029.0C19H23BrN2O (375.31)0.62
4gH4-OCH3171.6–173.030.0C20H26N2O2 (326.44)0.52
4hH4-CH3179.5–180.437.3C20H26N2O (310.44)0.66
4iHH174.4–175.254.5C19H24N2O (296.41)0.59
5aH4-OH289.6–290.544.0C18H22N2O2 (298.39)0.33
5cH4-OC2H5235.2–236.415.1C20H26N2O2 (326.44)0.59
5e3-NO24-Cl247.8–248.550.6C18H20ClN3O3 (361.83)0.55
5iHH186.9–187.260.5C18H22N2O (282.39)0.54
5j2-OH5-CH3247.6–248.860.4C19H24N2O2 (312.41)0.57
5k2-CH35-CH3283.5–284.035.5C20H26N2O (310.44)0.45
* Solvent: n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v), visualization at UV 254 nm.
Table
Table 2. Minimum inhibitory concentration (MIC) of synthesized hydrazide-hydrazones 4a–i and 5a–k.
Table 2. Minimum inhibitory concentration (MIC) of synthesized hydrazide-hydrazones 4a–i and 5a–k.
Comp. No.MIC of Synthesized Compounds (μM)
Gram (+)Gram (−)Fungus
EFSABCECPASECA
4a12.512.512.5---12.5
4b252525---25
4c252525---25
4d12.550100---6.25
4e255050---25
4f505050---12.5
4g2525100---25
4h252550---12.5
4i255050---25
5a12.52525---12.5
5c12.550100---12.5
5e252525---25
5i505050---50
5j505050---25
5k252525---25
STM35035017544350175NT
CHM NT NT NTNT NT NT 114
EF: Enterococcus faecalis (ATCC13124); SA: Staphylococcus aureus (ATCC25923); BC: Bacillus cereus (ATCC 13245); EC: Escherichia coli (ATCC25922); PA: Pseudomonas aeruginosa (ATCC27853); SE: Salmonella enterica (ATCC12228); CA: Candida albicans (ATCC10231); STM: streptomycine; CHM: Cycloheximide; NT: not tested; -: inactive.
Table
Table 3. IC50 of synthesized hydrazide-hydrazones 4a–i and 5a–k.
Table 3. IC50 of synthesized hydrazide-hydrazones 4a–i and 5a–k.
Comp. No.IC50 of Synthesized Compounds (μM)
Gram (+)Gram (−)Fungus
EFSABCECPASECA
4a6.356.776.12---6.37
4b11.5611.4512.56---12.78
4c13.2412.6712.77---13.11
4d6.8825.4552.11---3.56
4e13.5525.1125.99---13.57
4f24.7913.4425.33---6.77
4g12.5612.5556.7---11.55
4h13.2213.4523.88---6.45
4i12.5625.6625.65---12.33
5a6.7312.3312.37---6.25
5c6.7726.5526.78---6.66
5e13.2512.6712.33---13.22
5i25.6626.5526.56---25.33
5j24.5824.5624.33---11.45
5k12.3512.4512.33---13.46
EF: Enterococcus faecalis (ATCC13124); SA: Staphylococcus aureus (ATCC25923); BC: Bacillus cereus (ATCC 13245); EC: Escherichia coli (ATCC25922); PA: Pseudomonas aeruginosa (ATCC27853); SE: Salmonella enterica (ATCC12228); CA: Candida albicans (ATCC10231); -: inactive.
Table
Table 4. The effect of newly synthesized hydrazide-hydrazone 4a–i and 5a–k on the viability of HeP3B, Hela, A549, and MCF-7 cells after 48 h of incubation.
Table 4. The effect of newly synthesized hydrazide-hydrazone 4a–i and 5a–k on the viability of HeP3B, Hela, A549, and MCF-7 cells after 48 h of incubation.
Comp. No.Conc.Hep3BHelaA549MCF-7
4a30 µM63.89 ± 0.6973.09 ± 2.3167.78 ± 0.2663.28 ± 1.41
100 µM56.53 ± 1.3266.87 ± 1.1051.63 ± 0.8158.60 ± 0.32
4b30 µM66.83 ± 1.1582.84 ± 1.3766.89 ± 0.9464.32 ± 2.92
100 µM56.49 ± 2.1777.20 ± 0.9062.26 ± 0.1552.64 ± 2.02
4c30 µM80.62 ± 1.2593.64 ± 0.8877.76 ± 1.5179.36 ± 1.40
100 µM72.74 ± 2.0090.51 ± 1.2870.20 ± 0.1367.78 ± 0.95
4d30 µM96.80 ± 0.26>10065.33 ± 1.2890.20 ± 0.25
100 µM84.59 ± 2.3986.34 ± 1.3562.01 ± 2.3778.82 ± 2.22
4e30 µM94.59 ± 2.2080.07 ± 1.8764.43 ± 0.4960.94 ± 1.39
100 µM55.91 ± 1.7044.37 ± 1.3938.51 ± 1.5938.69 ± 1.20
4f30 µM>10088.26 ± 1.7476.22 ± 0.9894.68 ± 1.33
100 µM97.95 ± 2.4383.18 ± 0.2073.68 ± 1.0391.27 ± 2.26
4g30 µM91.63 ± 2.6396.61 ± 1.9887.40 ± 0.9583.11 ± 2.86
100 µM77.00 ± 1.8479.46 ± 1.2870.61 ± 1.6671.75 ± 1.71
4h30 µM98.29 ± 2.46>10078.42 ± 0.8391.59 ± 2.29
100 µM75.83 ± 2.7699.77 ± 1.8968.99 ± 2.3670.66 ± 2.57
4i30 µM81.96 ± 1.6788.70 ± 1.7968.43 ± 1.7259.77 ± 2.41
100 µM80.7 ± 2.1787.75 ± 0.2967.73 ± 1.8957.24 ± 0.75
5a30 µM87.03 ± 1.2887.53 ± 0.2169.08 ± 2.5686.14 ± 0.49
100 µM68.89 ± 2.1868.26 ± 2.0250.78 ± 1.8664.33 ± 1.76
5c30 µM88.96 ± 0.9189.07 ± 1.2190.47 ± 2.2370.30 ± 1.23
100 µM78.97 ± 1.8285.41 ± 1.3481.32 ± 1.2065.62 ± 0.64
5e30 µM57.77 ± 1.5976.75 ± 1.0736.42 ± 0.9452.56 ± 0.75
100 µM37.78 ± 2.4440.42 ± 0.3819.62 ± 1.7434.13 ± 2.22
5i30 µM83.16 ± 1.1989.12 ± 2.4379.49 ± 0.9471.53 ± 1.64
100 µM74.90 ± 1.3484.28 ± 2.1255.22 ± 1.6365.31 ± 1.66
5j30 µM92.80 ± 2.2468.96 ± 2.3878.71 ± 1.7586.48 ± 2.08
100 µM85.71 ± 2.2857.90 ± 1.3559.18 ± 2.0179.86 ± 2.13
5k30 µM98.51 ± 0.3882.96 ± 0.5962.55 ± 0.5991.80 ± 0.35
100 µM83.34 ± 1.6574.27 ± 1.6752.39 ± 1.5477.66 ± 1.54
CPT *0.3 μM69.56 ± 1.2757.06 ± 1.3567.68 ± 1.8856.68 ± 0.68
14.4 μM37.65 ± 1.2118.61 ± 0.5626.74 ± 2.1628.89 ± 1.07
* Camptothecine. Data is presented as percentage of the cell viability ± SD.

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Pham, V.H.; Phan, T.P.D.; Phan, D.C.; Vu, B.D. Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety. Molecules 2019, 24, 4000. https://doi.org/10.3390/molecules24214000

AMA Style

Pham VH, Phan TPD, Phan DC, Vu BD. Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety. Molecules. 2019; 24(21):4000. https://doi.org/10.3390/molecules24214000

Chicago/Turabian Style

Pham, Van Hien, Thi Phuong Dung Phan, Dinh Chau Phan, and Binh Duong Vu. 2019. "Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety" Molecules 24, no. 21: 4000. https://doi.org/10.3390/molecules24214000

APA Style

Pham, V. H., Phan, T. P. D., Phan, D. C., & Vu, B. D. (2019). Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety. Molecules, 24(21), 4000. https://doi.org/10.3390/molecules24214000

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