Synthesis and Synergistic, Additive Inhibitory Effects of Novel Spiro Derivatives Against Ringworm Infections
© 2013 Gajanand Sharma", *, Richa Sharma4, Anshu Dandiac, Preeti Bansal"
aDepartment of Chemical Sciences, Suresh Gyan Vihar University, Jaipur bDepartment of Biotechnology and Food Science, Jayoti Vidyapeeth Women's University, Jaipur cAnshu Dandia, Centre of Advanced Studies, Department of Chemistry, University of Rajasthan Received May 14, 2012; in final form November 12, 2012
An environmentally benign solvent free synthesis of various spiro-1,4-dihydropyridines (1,4-DHPs) incorporating 2-oxindole/piperidines is performed in 5—8 min with reasonable purity in 80—90% yield under microwave irradiation using montmorillonite KSF as an inorganic solid support. The reaction is found to be general with respect to various cyclic carbonyl compounds, e.g. cyclohexanone, substituted indole-2,3-dione, and pip-eridinone derivatives. In our study, these compounds were also found effective against dermatophytes and other fungal organisms. Our results suggest that novel spiro derivatives can be used for the treatment of dermatophy-tosis or ringworm infections.
Keywords: Montmorillonite KSF, microwave irradiation, MCRs, spiro-1,4-DHPs.
DOI: 10.7868/S0132342313030147
The rapid assembly of molecular diversity is an important goal of synthetic organic chemistry and one of key paradigms of modern drug discovery. One approach to address this challenge involves the use of multicom-ponent reactions (MCRs), in which three or more reac-tants are combined together in a single reaction flask to generate a product incorporating most of the atoms contained in the starting material. Due to their intrinsic atom economy, selectivity, simple procedures and equipment, time and energy saving, as well as environmental friendliness, MCRs are gaining much importance in both academia and industry [1—4].
Amlodipine [5, 8] is comparable — from a dynamic point ofview — to and nifedipine [6] and is in late stage clinical evaluation for the once-daily treatment of angina and hypertension [7]. Recent structure-activity assessment of a new generation of1,4-DHPs indicates that the presence of oxypropanolamine moiety on phenyl ring at position-4 of the DHP nucleus imparts the agents with P- or a-/P-adrenoceptor blocking activities [9,10]. In addition, Barnidipine and Furnid-ipine are well tolerated, as are other 1,4-DHP calcium channel anatagonists and vasodilators; headache, flushing, and peripheral oedema account for most of the adverse events reported [11]. Oedema is less frequent than with amlodipine and nitredipine. Also its use is not associated with reflex tachychardia. 1,4-Di-hydropyridine derivatives possess a variety of biological activities such as HIV protease inhibition [12, 13],
* Corresponding author: e-mail: gnsharma2020@gmail.com
MDR reversal [14—16], radioprotection [17], vasodila-ton [18], antitumor, bronchodilator, and hepatoprotec-tive activities [19]. A large number of publications is available on the synthesis of these biodynamic scaffolds [20].
Spirooxindole derivatives are also becoming key building blocks for drug discovery as these templates have been shown to exhibit a variety of interesting biological activities, such as antioneoplastic [21], antibiotic [22], cytostatic [23], monoamine transporter inhibiting [24], bradykinin antagonist [25], and cell cycle inhibiting activities [26]. Due to their structure, they interact with a wide range of receptors and this activity has resulted in significant interest in developing efficient methods to prepare spirocompounds. On the other hand, spiropiperidines have also received great attention because of their promising therapeutic applications [27—30]. The spiro(indoline-3,4'-piperidine) scaffold is a key structural feature in MK-0677, a potent peptidomimetic growth hormone secretagogue (GHS) [31], a serine-derived NK1 antagonist, and a potent and selective melanocortin subtype-4 (MC-4) receptor agonist [32]. It is also found in oxytocin, somatostatin, ta-chykinines, anaphylatoxin chemotactic receptor ligands, and is considered as a privileged structure for general G-protein coupled receptor (GPCR) ligands [33].
To the best of our knowledge, no work has been reported on the multicomponent synthesis of spiro-1,4-DHPs incorporating N-substituted piperidine or 2-oxindoline motif in a single molecular framework.
Hence, promoted by these observations and in continuation of our earlier interest on the green chemical synthesis of biodynamic spiro and annulated derivatives [34, 35] using non-traditional approach, an attempt has been made to synthesize various spiro-1,4-DHP derivatives with the assumption that the incorporation of more than one bioactive heterocyclic moiety into a sin-
gle framework may result in the production of novel het-erocycles with enhanced/altered bioactivity. Therefore, we herein report novel spiro derivatives combining heterocyclic moieties with 1,4-DHPs by the multicompo-nent reaction of cyclic carbonyl compounds (1), P-ke-toester (2), and substituted anilines (3), as depicted in Scheme, using environmentally benign methodologies.
COOC2H5 CH3
>
>o
H
H
O
+
COOC2H5 CH3
Mont. KSF
MW
COOC2H5 CH3
nh2
\
X
CH3 COOC2H5
4
X
O
>-o
O
4a; X = 4-OC2H5
N
I
CH3 4b; X = 4-CH
3
O
Y-
O
N CH2Ph 4c; X = 4-Cl
N "O
H
4d; X = 4-Cl, Y = H 4e; X = H Y = 5-CH3 4f; X = 4-CH3, Y = 4-Cl
Scheme.
2
3
A series of novel N-substituted spiro-1,4-dihydro-pyridines (4a—4f) have been synthesized in one pot under microwave irradiation using solvent-free conditions (Table 1). The reaction was performed under different conditions to find out the best method giving product in higher yield with operational simplicity. In the present investigation, we study the synthesis of 3-(4-ethox-yphenyl)-2,4-dimethyl-3-azaspiro[5.5]undeca-1,4-di-ene-1,5-dicarboxylic acid diethyl ester (4a) via multi-component reaction of cyclohexanone (1), P-ketoester (2), and p-phenatidine (3) varying the reaction parameters as shown in Table 2.
Results reported in Table 2 evidence that the multi-component reaction of (1), (2), and (3a) occurred successfully in ethanol without using any catalyst both under microwave irradiation and conventionally. However, the
yield of the product was low when the reaction was carried out conventionally in ethanol. The reaction was also performed under neat conditions without adding any solvent or support, which could be expected to be the most economical method. The reaction proceeded efficiently (~100% conversion, indicated by TLC) but the yield ofisolated crystalline product decreased to 72% due to the tedious work-up procedure which requires trituration with petroleum ether followed by crystallization from methanol.
To further improve the procedure, reaction was also studied using different types of inorganic solid supports, e. g., montmorillonite KSF, neutral alumina, and silica gel. The montmorillonite KSF was found to be the best solid support giving the maximum (90%) yield of the required product reasonable purity (TLC) with shortest
Table 1. Novel spiro-1,4-DHP derivatives
Entry Reactants Product
(1) (2) ( 3)
(4a) O Ô O O nh2 <h OC2H5 C2H5OOC_ CH3 qq^OC2H5 C2H5OOC CH3
(4b) O 0 CH3 O O nh2 Ch CH3 C2H5OOC_ CH3 H3C^^C)3 C2H5OOC CH3
(4c) O 0 CH2Ph O O nh2 Ch Cl C2H5OOC CH3 Ph)2C^N^Cl C2H5OOC CH3
(4d) Wo H O O nh2 Ch Cl C2H5OOC ctf H CH3 ^C)3 COOC2H5
(4e) Wo H O O nh2 cN) CH3 CjHjOOojs —/=\ HN O COOC2H5
(4f) Wo H O O nh2 <> CH3 C2H5OOC^ ClYV~ H CH3 V^C)3 3 COOC2H5
time and easier work-up (Table 2). However, for spectral studies and elemental analyses, compounds (4a—4f) were recrystallized from methanol.
The three-component condensation of cyclic ketones (1), P-ketoester (2), and substituted anilines (3) gave corresponding spiro-1,4-dihydropyridine derivatives incorporating indoline/piperiding ring.
The structure assigned for the reaction product is established from analytical and spectral data. The IR spectrum of spiro compounds displayed characteristic absorption band in the region of 1694—1724 cm-1 due to C=O vibrations. Aromatic and aliphatic C-H absorption bands were observed at 3080-3060 and 29852960 cm-1, respectively. The aromatic skeletal vibrations of C-C appeared at 1600, 1580, and 1450 cm-1
Table 2. Comparative results obtained in the synthesis of (4a) using classical method (A) and microwave assistance (MW)
Exp. Medium Mode of activation Time (min) Temp.a (°C) Yieldb (%)
1 EtOH MW 15 78 85
2 Neat MW 5 135 72
3 Neutral alumina MW 7 120 70
4 Acidic alumina MW 8 122 78
5 Silica gel MW 10 125 70
6 Mont. KSF MW 6 138 90
7 EtOH + AcONa A 600-840 Reflux 50
a Final temperature is measured at the end of MW irradiation by introducing a glass thermometer in the reaction mixture. b Isolated yield.
Table 3. Antifungal activity of compounds (the newly synthesized spiro-1,4-DHPs derivatives (4a—4f)) against Trichophyton rubrum
Compound Concentration of compounds, % IZ of sample, mm IZ of a standard (Ketocona-zole), mm AI IZ of a standard (Clotrimazole), mm AI
(4a) 100 68 60 1.1 36 1.8
(4b) 100 72 60 1.2 36 2.0
(4c) 100 82 60 1.3 36 2.2
(4d) 100 80 60 1.3 36 2.2
(4e) 100 79 60 1.3 36 2.1
(4f) 100 78 60 1.3 36 2.1
and the broad and intense absorption, occurred at 1595—1610 cm-1 in all spectra, was assigned to C=C stretching. 1H NMR spectra of compounds (4a—4f) exhibited one sharp singlet at 8.05 ppm due to NH proton along with a multiplet at 7.09—7.26 ppm for the aromatic protons. A triplet and a quartet appeared at 1.15— 1.28 ppm and 4.03—4.10 ppm due to the presence of methyl and methylene protons of carbethoxy group, respectively. A singlet was found at 2.32 ppm due to the methyl protons. The presence and position of NH was confirmed with deuteration.
Further, the structure of spiro compounds was also supported by 13C NMR and mass spectra. In the 13C NMR spectrum of(4a) the quaternary C-6 spiro carb
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