1, 2-Benzo[d]isothiazol-3(2H)-one (BIT) is an anti-bacterial and anti-algae agent[1-4] with the characteristics of high efficiency, low toxicity, small dosage and long efficacy. However, its poor solubility in a large number of non-polar organic solvents and poor compatibility with organic materials limit the use of BIT in non-water-based products such as coatings, plastics, composite materials, and so on. To improve the lipophilic property and enhance the bioactivity, several N-alkyl derivatives[5-7] of BIT, including N-methyl-1, 2-benzo[d]isothiazol-3(2H)-one (MBIT), N-butyl-1, 2-benzo[d]isothiazol-3(2H)-one (BBIT) and N-octanyl-1, 2-benzo-[d]isothiazol-3(2H)-one (OBIT), were synthesized.
Longifolene, a main component of heavy turpentine, is an important natural tricyclic sesquiterpene, which has significant application and development prospect in spices, pesticide and medicine. Firstly, it has been mainly used to synthesize spices[8] with an ambergris-woody odor. Moreover, it shows strong lipophilic property and has been used as a low toxicity, environmentally friendly solvent in wash oil-soluble and emulsion pesticide[9]. Furthermore, it shows certain biological activities[10-13] such as antibacterial, antibacterial, anti-inflammatory, anti-cancer and algae-inhibiting, and has shown good applications in medicine, pesticide and other industries. In addition, ω-chloromethyl longifolene[14] can be thought of as an allyl chloride compound, which contains natural longifolene molecule structure moiety and chemically active allyl chloride functional group, resulting in improved hydrophilic property and antimicrobial activity against bacterium and fungi than nature longifolene.
On the basis of our previous work, the title compound (Ic) is synthesized through inducing a natural longifolene molecule structure moiety into BIT and its solubility and hydrophilicity/lipophilicity are investigated. Herein, spectro-scopic and molecule crystal structure data are reported. Besides, the antimicrobial activities have also been discussed.
Longifolene with GC purity over 85% and compound Ia were prepared from heavy turpentine according to the previous works[15, 16]. All chemicals were of reagent grade and used directly without further purification. Two Gram-positive bacteria (S. aureus (ATCC-25923) and B. subtilis (ATCC-6633)), two Gram-negative bacteria (E. coli (ATCC-8739) and K. pneumoniae (ATCC-4352)) and three fungi (C. albicans (ATCC-10231), C. tropicalis (ATCC-13803) and A. niger (ATCC-16404)) were purchased from the Beijing Beina Chuanglian Biotechnology Research Institute (Beijing, China).
IR spectra were obtained on a Magna-IR 550 Fourier transform infrared spectrometer (Nicolet Co., Ltd., USA) in the 400~4000 cm–1 region using KBr pellets. The melting point was determined on an XT-4 apparatus (Beijing Taike Corp., Beijing, China) without correction for the thermometer. NMR spectra were recorded on a JEOL JNM-ECZ600R spectrometer (JEOL Ltd, Tokyo, Japan) using CDCl3 as solvent with TMS as the internal standard. High-resolution mass spectra (HRMS, ESI+) were recorded on an Agilent 6224 Accurate-Mass TOF LC/MS (Agilent Technologies, USA). The diffraction data was cedollect on an Agilent Gemini E single crystal X-ray diffractometer (Agilent Technologies, Santa Clara, USA). The LogP value was calculated by using ChemBioDraw Ultr 12.0 software.
According to the allyl chlorides synthetic procedure[17], acetyl chloride (0.02 mol) was added dropwise with stirring between drops to a solution of compound Ia (0.01 mol) and absolute ethyl alcohol (0.03 mol). Then, the mixture was heated to reflux at 30 ℃ for 10 min. After the reaction, the resulting mixture was rotary evaporated under reduced pressure to remove the components with low boiling point and give a light brown oily raw product. The raw product was dissolved in chloroform and washed in distilled water for several times until pH = 7. The organic phase was evaporated to recycle solvent and compound Ib was obtained. ω-Chloromethyl longifolene (Ib). Light brown oil, yield 85%. HRMS (ESI+) [M-Cl]+, calcd. for C16H25, 217.1956, found 217.1963, Δ = 0.36 ppm. FT-IR (liquid film) v: 3037 (w, ν(=C–H)), 2954 (s, νas(C–H)), 2864 (s, νs(C–H)), 1680 (s, ν(C=C)) cm–1; 1H NMR (CDCl3, 600 MHz) δ: 5.1~5.18 (1H, t, J = 6.0Hz, H-13), 4.12~4.13 (2H, dd, J = 6.0Hz, H-14), 2.93~2.94 (1H, d, J = 6.0Hz, H-1), 2.07~2.08 (1H, d, J = 6.0Hz, H-2eq), 1.70~1.76 (1H, m, H-3eq), 1.58~1.68 (3H, m, H-6eq, H-4a, H-8a), 1.48~1.55 (2H, m, H-6ax, H-2ax), 1.39~1.46 (3H, m, H-3ax, H-5eq, H-7eq), 1.01~1.08 (2H, m, H-5ax, H-7ax), 1.00 (3H, s, H-10), 0.97 (3H, s, H-11), 0.88 (3H, s, H-12).
Compound Ib (0.01 mol) in DMF (50 mL) was added dropwise with stirring between drops to a solution of 1, 2-benzoisothiazolinone (0.01 mol) and NaOH (0.01 mol) in DMF (50 mL). Then, the mixture was heated to reflux at 100 ℃ for 3 h. After the reaction, the resulting mixture was successively rotary evaporated under reduced pressure to remove the solvent, and washed for three times with water and petroleum ether, respectively. A light brown power crude product was collected via filtration and vacuum dried. This crude product was purified by re-crystallization in petroleum ether.
(E)-2-(2-(4, 8, 8-trimethyldecahydro-1, 4-methanoazulen-9-ylidene)ethyl)benzo[d]isothiazol-3(2H)-one (Ic). Reddish-brown powder, yield 75.6%, mp. 118.7~119.3 ℃; HRMS (ESI+) [M+Na]+, calcd. for C23H29NONaS 390.1862, found 390.1854, Δ = 2.08 ppm. FT-IR (KBr) v: 3060 (w, ν(=C–H)), 2948 (s, νas(C–H)), 2864 (s, νs(C–H)), 1658 (s, ν(C=O)), 1507 (s, ν(C=C)), 1453 (m, δ(C–H)), 1165(s, ν(C–O)), 733(s, γ(C–H)) cm–1; 1H NMR (600 MHz, CDCl3) δ: 8.03~8.04 (d, J = 6.0Hz, 1H, H-9΄), 7.53~7.57 (m, 2H, H-6΄, H-7΄), 7.35~7.37 (m, 1H, H-8΄), 5.13~5.15 (t, J = 6.0Hz, 1H, H-13), 4.50~4.58 (m, 2H, H-14), 3.05~3.06 (d, J = 6.0Hz, H-1), 2.13~2.14 (d, J = 6.0Hz, 1H, H-4a), 1.76~1.81 (m, 1H, H-8a), 1.63~1.72 (m, 3H, H-6eq, H-2eq, H-3eq), 1.52~1.57 (m, 3H, H-3ax, H-2ax, H-6ax), 1.42~1.49 (m, 2H, H-5eq, H-7eq), 1.12~1.18 (m, 1H, H-5ax), 1.07~1.11 (m, 1H, H-7ax), 1.02 (s, 3H, H-10), 0.97 (s, 3H, H-11), 0.93 (s, 3H, H-12). 13C NMR (150MHz, CDCl3) δ: 165.70 (C-3΄), 140.52 (C-9), 131.50 (C-4΄), 126.57 (C-7΄), 125.34 (C-8΄, C-5΄, C-9΄), 120.45 (C-6΄), 109.37 (C-13), 62.76 (C-8a), 49.59 (C-4a), 42.46 (C-14), 36.71 (C-1), 33.64 (C-5, C-7), 31.02 (C-2), 30.40 (C-4), 30.21 (C-8), 28.87 (C-11, C-12), 25.60 (C-6, C-3), 21.04 (C-10).
Single crystals of compound Ic for X-ray diffraction analyses were grown by slow evaporation technique in absolute ethanol solvent at room temperature. A white crystal (0.3mm × 0.2mm × 0.18mm) was mounted on a glass fiber for data collection at 173 K with an Agilent Gemini Ediffractometer (Mo, 50 kV, 40 mA). Absorption corrections were applied using multi-scan technique, supplied by George Sheldrick.The structures were solved by direct methods using SHELXS-97. Refinements were performed with SHELXL-2013 using fullmatrix least-squares calculations on F2, with anisotropic displacement parameters for all the non-hydrogen atoms. A total of reflections were collected in the range of 2.74≤θ≤26.00°, in which 17045 were independent with Rint = 0.0566 and 7306 observed reflections with I > 2σ(I) were used in the structure determination and refinements. The final refinement including hydrogen atoms was converged to R = 0.0967, wR = 0.1998 (w = 1/[σ2(Fo2) + (0.0938P)2 + 2.5514P], where P = (Fo2 + 2Fc2)/3), (Δ/σ)max = 0.000, S = 1.030, (Δρ)max = 0.244 and (Δρ)min = –0.327 e·Å–3.
The antimicrobial activities of the compounds were evaluated by measuring the minimum inhibitory concentration value (MIC) against two Gram-positive bacteria S. aureus (ATCC-25923) and B.subtilis (ATCC-6633), two Gram-negative bacteria E. coli (ATCC-8739) and K. pneumoniae (ATCC-4352), three fungi C. albicans (ATCC-10231), C. tropicalis (ATCC-13803), A. niger (ATCC-16404). Luria-Bertani (LB) broth and potato dextrose broth (PDB) were used as the culture media of bacteria and fungi, respectively. The MIC of the test compound was determined by the 96-well plate micro-broth dilution method[18].
Nitro-substituted derivatives of 1, 2-benzoisothiazolinone could be prepared from alkyl halide or allyl halide via substitution at nitrogen atom. Generally, reacting 1, 2-benzoisothiazolinone with sodium hydroxide in alcohol solvent gave 1, 2-benzoisothiazolinone sodium salt and the result solution was added alkyl halide or allyl halide for synthesizing nitrogen substitution derivatives[7]. However, compound Ib could partly be converted into allyl ethyl ethers as by-product because of its similar chemical activity with allyl halides, thus reducing the yield of main product nitrogen substitution derivative and a complicated process for separation and purification. N, N-dimethylformamide (DMF) was used as solvent to replace alcohol for synthesizing compound Ic with a good yield of 85%.
Compound Ic was purified by re-crystallization and structurally identified by means of HRMS, IR, 1H-NMR, 13C-NMR, and single-crystal X-ray diffraction. For example, the molecular formula of compound Ic was determined as C23H29NONaS through the data of HRMS (ESI+) spectrum (m/z 390.1854 [M+Na] +). The IR spectrum of compound Ic exhibits strong absorption bands at 2948 and 2864 cm–1, corresponding to the C–H stretching of sp3 carbon atoms of 2-(4, 8, 8-trimethyldecahydro-1, 4-methanoazulen-9-ylidene)et-hyl moiety. The strong absorption bands at 1658 and 1507 cm–1 are due to the C=O stretching vibration and benzene ring skeleton stretching vibration of the 1, 2-benzoisothiazolinone moiety, respectively. The medium absorption bands at 3060 cm–1 are due to the C–H stretching of sp2 carbon atoms. In its 1H-NMR spectrum, three singlets at δ 1.02, 0.97, and 0.93 ppm can be observed, corresponding to methyl protons at C-10, C-11 and C-12, respectively. The triplet peaks containing one proton at δ 5.13~5.15 ppm can be attributed to the allyl hydrogen at C-13 and the multiple peaks containing two protons at δ 4.50~4.58 ppm are assigned to the allyl hydrogens at C-14. In addition, three sets of peaks containing four protons in a range of δ 7.35~8.04 ppm can be assigned to the aromatic hydrogens. The 13C-NMR spectrum of compound Ic exhibits 23 well resolved resonances of 23 carbon atoms. Among them, the carbonyl carbon (C-3΄) appears at δ 165.70 ppm. Six aromatic carbons (C-4΄, C-7΄, (C-8΄, C-5΄, C-9΄), C-6΄) are observed at δ 131.50, 126.57, 125.34 and 120.45 ppm, respectively. Moreover, two peaks at δ 140.52 and 109.37 ppm are confirmed to be the signals of C-9 and C-13 in the 2-(4, 8, 8-trimethyldecahydro-1, 4-methanoazulen-9-ylidene)ethyl moiety, respectively. The assignments of the signals in the 1H and 13C NMR spectra of compound Ic are in good accordance with its structure.
The crystal and molecule structure of compound Ic with atom-numbering scheme is given in Fig. 1, and the selected bond lengths and bond angles are given in Table 1. As shown as Fig. 1, this crystal is of bi-molecular structure. The molecule consists of a 1, 2-benzoisothiazolinone moiety and a 2-(4, 8, 8-trimethyldecahydro-1, 4-methanoazulen-9-ylidene)et-hyl moiety, which are connected through the N(1) and the C(8) atoms or through the N(2) and C(31) atoms. The bond length of N(1)–C(8) is 1.498(10) Å, while the bond length of N(2)–C(31) is 1.483(10) Å. The bond angle of S(1)–N(1)–C(8) is 118.2(5)°, while the bond angle of S(2)–N(2)–C(31) is 117.0(5)°. Other bond lengths and angles have similar phenomena as Table 1, suggesting that the two molecules in each asymmetric unit are obviously asymmetric.
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| Bond | Dist. | Bond | Dist. | Bond | Dist. | ||
| S(2)–N(2) | 1. 707(7) | O(1)–C(1) | 1. 240(10) | C(27)–C(28) | 1. 284(14) | ||
| S(2)–C(30) | 1. 767(8) | N(1)–C(8) | 1. 498(10) | N(2)–C(24) | 1. 361(10) | ||
| S(1)–N(1) | 1. 718(8) | N(1)–C(1) | 1. 359(11) | C(24)–C(25) | 1. 476(12) | ||
| S(1)–C(7) | 1. 734(9) | C(32)–C(31) | 1. 476(13) | C(7)–C(6) | 1. 399(13) | ||
| C(11)–C(10) | 1. 518(9) | C(2)–C(7) | 1. 383(13) | C(28)–C(29) | 1. 381(13) | ||
| C(34)–C(33) | 1. 494(10) | C(2)–C(3) | 1. 346(12) | C(6)–C(5) | 1. 417(15) | ||
| C(10)–C(14) | 1. 480(12) | C(2)–C(1) | 1. 451(11) | C(25)–C(30) | 1. 378(13) | ||
| C(10)–C(9) | 1. 333(11) | C(9)–C(8) | 1. 472(13) | C(30)–C(29) | 1. 367(12) | ||
| O(2–C(24) | 1. 236(10) | C(26)–C(27) | 1. 427(14) | C(3)–C(4) | 1. 390(12) | ||
| C(33)–C(37) | 1. 494(11) | C(26)–C(25) | 1. 388(12) | ||||
| C(33)–C(32) | 1. 372(9) | C(31)–N(2) | 1. 483(10) | ||||
| Angle | (°) | Angle | (°) | Angle | (°) | ||
| N(2)–S(2)–C(30) | 90.1(4) | C(1)–N(1)–C(8) | 124.8(7) | C(27)–C(28)–C(29) | 120.9(9) | ||
| N(1)–S(1)–C(7) | 90.0(4) | C(33)–C(32)–C(31) | 125.5(9) | C(7)–C(6)–C(5) | 114.9(10) | ||
| C(10)–C(11)–C(12) | 101.9(6) | C(7)–C(2)–C(1) | 113.6(7) | C(9)–C(8)–N(1) | 109.1(8) | ||
| C(10)–C(11)–C(20) | 113.8(6) | C(3)–C(2)–C(7) | 119.4(8) | C(26)–C(25)–C(24) | 127.1(8) | ||
| C(10)–C(11)–C(23) | 111.5(6) | C(3)–C(2)–C(1) | 126.6(9) | C(30)–C(25)–C(26) | 117.1(9) | ||
| C(33)–C(34)–C(35) | 101.0(6) | C(10)–C(9)–C(8) | 125.3(11) | C(30)–C(25)–C(24) | 115.7(7) | ||
| C(33)–C(34)–C(46) | 110.8(6) | C(25)–C(26)–C(27) | 116.8(9) | C(25)–C(30)–S(2) | 109.7(7) | ||
| C(33)–C(34)–C(40) | 114.0(6) | C(32)–C(31)–N(2) | 110.5(8) | C(29)–C(30)–S(2) | 126.0(7) | ||
| C(14)–C(10)–C(11) | 105.2(6) | C(28)–C(27)–C(26) | 123.4(9) | C(29)–C(30)–C(25) | 124.2(8) | ||
| C(9)–C(10)–C(11) | 123.8(9) | C(31)–N(2)–S(2) | 117.0(5) | C(2)–C(3)–C(4) | 119.1(9) | ||
| C(9)–C(10)–C(14) | 130.6(8) | C(24)–N(2)–S(2) | 117.9(6) | O(1)–C(1)–N(1) | 122.5(8) | ||
| C(34)–C(33)–C(37) | 107.2(5) | C(24)–N(2)–C(31) | 125.1(7) | O(1)–C(1)–C(2) | 128.8(8) | ||
| C(32)–C(33)–C(34) | 125.4(8) | O(2–C(24)–N(2) | 127.1(8) | N(1)–C(1)–C(2) | 108.6(8) | ||
| C(32)–C(33)–C(37) | 127.3(8) | O(2)–C(24)–C(25) | 126.3(7) | C(30)–C(29)–C(28) | 117.1(9) | ||
| C(33)–C(37)–C(36) | 102.9(6) | N(2)–C(24)–C(25) | 106.4(7) | C(4)–C(5)–C(6) | 121.0(10) | ||
| C(33)–C(37)–C(38) | 106.8(7) | C(2)–C(7)–S(1) | 111.6(7) | C(5)–C(4)–C(3) | 122.2(9) | ||
| C(8)–N(1)–S(1) | 118.2(5) | C(2)–C(7)–C(6) | 123.4(8) | ||||
| C(1)–N(1)–S(1) | 116.1(6) | C(6)–C(7)–S(1) | 125.1(8) |
In the whole structure, there are two antiparallel-displaced (also known as offset face-to-face) π-π interactions[19, 20] between the neighboring benzene rings (C(2)~C(7)) and (C(25)~C(30)) from adjacent molecules, which are approximately parallel to each other with an equal dihedral angle of 3.317(4)° and different centroid-to-centroid distances, as shown in Fig. 2. A π-π interaction (pink thick dashed line) with a centroid-to-centroid distance of 3.812 Å and the shortest perpendicular distance of 3.662 Å for the centre of one benzene ring to the plane of the other links two adjacent molecules to form a dimer. Another π-π stacking interaction (cyan thin dashed line) with a centroid-to-centroid distance of 4.299 Å and the shortest perpendicular distance of 3.772 Å connects adjacent dimmers together to form the extended 1D chain along the a direction. The centroid- to-centroid distances of 3.812 and 4.299 Å are more than that of conventional aromatic π-π stacking interactions (3.3~3.6 Å) but less than the upper limit distance of what is normally considered π-π stacking[21-23], indicating that the correspon- ding intermolecular interactions are relatively weak.
The π-π stacking interactions have a very pronounced effect on molecular structure and properties. π-π interactions connect the adjacent molecules to form a 1D chain with exposed non-polar moiety and the sandwiched polar moiety, resulting in that compound Ic has lower melting point and shows more lipophilicity than BIT and could be dissoluble in non-polar organic solvents, as shown in Table 2. The LogP values of compound Ic and BIT being respectively 8.16 and 2.14 are also consistent with the fact that compound Ic shows improved lipophilic property than BIT.
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| Comp. | LogP | Solubility in different organic solvents | ||||||||
| Ethyl alcohol | Ethyl acetate | Chloroform | Benzene | Xylene | Coating thinner | Ethyl ether | Turpinene | Petroleum ether | ||
| I | 7.17 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I a | 6.86 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I b | 7.42 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I c | 8.16 | ++ | ++ | ++ | ++ | ++ | + | + | － | －－ |
| BIT | 1.27 | ++ | ++ | ++ | － | － | － | － | － | －－ |
| Note: －－, indissolvable; －, slight soluble; +, soluble; ++, freely soluble | ||||||||||
The results of antimicrobial activity assay of compound Ic are shown in Table 3. Compound Ic shows obvious antimicro- bial activity against bacterium and fungi. The minimum inhibitory concentration (MIC) of compound Ic against S. aureus, B.subtilis, E. coli, K. pneumoniae, C. albicans, C. tropicalis, and A.niger are 15.6, 15.6, 0.242, 0.242, 1.95, 1.95 and 1.95 µg/mL, respectively. Compound Ic shows similar or improved antimicrobial activity against all aforementioned bacteria and fungi than BIT, in which the MIC values are 3.91, 7.81, 0.977, 0.483, 3.91, 7.81 and 3.91 µg/mL, respectively. Furthermore, compound Ic displays remarkably higher antimicrobial activity than longifolene and compounds Ia-b, indicating that introducing longifolene molecule structure into BIT plays a synergistic enhancement role on the antimicrobial activity.
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| Comp. | MIC (µg/mL) | ||||||
| E.coli | K.pneumoniae | S.aureus | B.subtilis | C.albicans | C.tropicalis | A.niger | |
| I | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 |
| I a | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 |
| I b | 62.5 | 31.3 | 7.81 | 15.63 | 125 | 15.6 | 62.5 |
| I c | 15.6 | 15.6 | 0.242 | 0.242 | 1.95 | 1.95 | 1.95 |
| BIT | 3.91 | 7.81 | 0.977 | 0.483 | 3.91 | 7.81 | 3.91 |
The synergistic enhancement of longifolene molecule structure on the antimicrobial activity of BIT could be related with the lipophilic property. Firstly, the longifolene shows good lipophilicity and can inhibit the growth of a variety of bacteria and fungi[12, 13]. Secondly, compound Ic shows improved lipophilicity than BIT, in which the logP values of the former and the latter are 8.16 and 1.27, respectively (Table 3). It indicates that compound Ic displays more dissolution or dispersion in no-polar organic solvent than BIT and may be used as an oil-soluble antibacterial agent for paint, coating, leather and other products.
In conclusion, compound Ic was synthesized from longifolene and BIT through Prins, halogenation and nitro- alkylation reaction and structurally identified. Compound Ic is more soluble in non-polar organic solvents than BIT. Especially, compound Ic showed higher antimicrobial activity than longifolene and BIT against bacteria and fungi, and could have potential as a antimicrobial agent in lipophilic form.
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Scheme 1 Synthetic route for compound Ic: (a) Longifolene, acetic acid glacial, (HCOH)n, heated at 110 ℃ for 24 h; (b) Compound Ia, acetyl chloride, anhydrous ethanol, heated at 30 ℃ for 30 min; (c) Compound Ib, BIT, NaOH, DMF, reflux
Figure 1 Molecular structure of the title compound with atom-numbering scheme. For clarity, the H atoms have been omitted
Figure 2 A packing diagram for the title compound viewed along the b-axis. The π-π interactions between benzene rings from an asymmetric unit (pink thin dashed lines) and adjacent asymmetric units (cyan thin dashed lines) are found respectively
Table 1. Selected Bond Lengths (Å) and Bond Angles (°) for Compound Ic
| Bond | Dist. | Bond | Dist. | Bond | Dist. | ||
| S(2)–N(2) | 1. 707(7) | O(1)–C(1) | 1. 240(10) | C(27)–C(28) | 1. 284(14) | ||
| S(2)–C(30) | 1. 767(8) | N(1)–C(8) | 1. 498(10) | N(2)–C(24) | 1. 361(10) | ||
| S(1)–N(1) | 1. 718(8) | N(1)–C(1) | 1. 359(11) | C(24)–C(25) | 1. 476(12) | ||
| S(1)–C(7) | 1. 734(9) | C(32)–C(31) | 1. 476(13) | C(7)–C(6) | 1. 399(13) | ||
| C(11)–C(10) | 1. 518(9) | C(2)–C(7) | 1. 383(13) | C(28)–C(29) | 1. 381(13) | ||
| C(34)–C(33) | 1. 494(10) | C(2)–C(3) | 1. 346(12) | C(6)–C(5) | 1. 417(15) | ||
| C(10)–C(14) | 1. 480(12) | C(2)–C(1) | 1. 451(11) | C(25)–C(30) | 1. 378(13) | ||
| C(10)–C(9) | 1. 333(11) | C(9)–C(8) | 1. 472(13) | C(30)–C(29) | 1. 367(12) | ||
| O(2–C(24) | 1. 236(10) | C(26)–C(27) | 1. 427(14) | C(3)–C(4) | 1. 390(12) | ||
| C(33)–C(37) | 1. 494(11) | C(26)–C(25) | 1. 388(12) | ||||
| C(33)–C(32) | 1. 372(9) | C(31)–N(2) | 1. 483(10) | ||||
| Angle | (°) | Angle | (°) | Angle | (°) | ||
| N(2)–S(2)–C(30) | 90.1(4) | C(1)–N(1)–C(8) | 124.8(7) | C(27)–C(28)–C(29) | 120.9(9) | ||
| N(1)–S(1)–C(7) | 90.0(4) | C(33)–C(32)–C(31) | 125.5(9) | C(7)–C(6)–C(5) | 114.9(10) | ||
| C(10)–C(11)–C(12) | 101.9(6) | C(7)–C(2)–C(1) | 113.6(7) | C(9)–C(8)–N(1) | 109.1(8) | ||
| C(10)–C(11)–C(20) | 113.8(6) | C(3)–C(2)–C(7) | 119.4(8) | C(26)–C(25)–C(24) | 127.1(8) | ||
| C(10)–C(11)–C(23) | 111.5(6) | C(3)–C(2)–C(1) | 126.6(9) | C(30)–C(25)–C(26) | 117.1(9) | ||
| C(33)–C(34)–C(35) | 101.0(6) | C(10)–C(9)–C(8) | 125.3(11) | C(30)–C(25)–C(24) | 115.7(7) | ||
| C(33)–C(34)–C(46) | 110.8(6) | C(25)–C(26)–C(27) | 116.8(9) | C(25)–C(30)–S(2) | 109.7(7) | ||
| C(33)–C(34)–C(40) | 114.0(6) | C(32)–C(31)–N(2) | 110.5(8) | C(29)–C(30)–S(2) | 126.0(7) | ||
| C(14)–C(10)–C(11) | 105.2(6) | C(28)–C(27)–C(26) | 123.4(9) | C(29)–C(30)–C(25) | 124.2(8) | ||
| C(9)–C(10)–C(11) | 123.8(9) | C(31)–N(2)–S(2) | 117.0(5) | C(2)–C(3)–C(4) | 119.1(9) | ||
| C(9)–C(10)–C(14) | 130.6(8) | C(24)–N(2)–S(2) | 117.9(6) | O(1)–C(1)–N(1) | 122.5(8) | ||
| C(34)–C(33)–C(37) | 107.2(5) | C(24)–N(2)–C(31) | 125.1(7) | O(1)–C(1)–C(2) | 128.8(8) | ||
| C(32)–C(33)–C(34) | 125.4(8) | O(2–C(24)–N(2) | 127.1(8) | N(1)–C(1)–C(2) | 108.6(8) | ||
| C(32)–C(33)–C(37) | 127.3(8) | O(2)–C(24)–C(25) | 126.3(7) | C(30)–C(29)–C(28) | 117.1(9) | ||
| C(33)–C(37)–C(36) | 102.9(6) | N(2)–C(24)–C(25) | 106.4(7) | C(4)–C(5)–C(6) | 121.0(10) | ||
| C(33)–C(37)–C(38) | 106.8(7) | C(2)–C(7)–S(1) | 111.6(7) | C(5)–C(4)–C(3) | 122.2(9) | ||
| C(8)–N(1)–S(1) | 118.2(5) | C(2)–C(7)–C(6) | 123.4(8) | ||||
| C(1)–N(1)–S(1) | 116.1(6) | C(6)–C(7)–S(1) | 125.1(8) |
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Table 2. Solubility and Lipophilic Property of Compound Ic
| Comp. | LogP | Solubility in different organic solvents | ||||||||
| Ethyl alcohol | Ethyl acetate | Chloroform | Benzene | Xylene | Coating thinner | Ethyl ether | Turpinene | Petroleum ether | ||
| I | 7.17 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I a | 6.86 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I b | 7.42 | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
| I c | 8.16 | ++ | ++ | ++ | ++ | ++ | + | + | － | －－ |
| BIT | 1.27 | ++ | ++ | ++ | － | － | － | － | － | －－ |
| Note: －－, indissolvable; －, slight soluble; +, soluble; ++, freely soluble | ||||||||||
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Table 3. Inhibition of Compound Ic against Bacterium and Fungi
| Comp. | MIC (µg/mL) | ||||||
| E.coli | K.pneumoniae | S.aureus | B.subtilis | C.albicans | C.tropicalis | A.niger | |
| I | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 |
| I a | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 | > 500 |
| I b | 62.5 | 31.3 | 7.81 | 15.63 | 125 | 15.6 | 62.5 |
| I c | 15.6 | 15.6 | 0.242 | 0.242 | 1.95 | 1.95 | 1.95 |
| BIT | 3.91 | 7.81 | 0.977 | 0.483 | 3.91 | 7.81 | 3.91 |
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