SYNTHESIS, REACTIONS, AND BIOLOGICAL ACTIVITY OF SOME TRIAZINE DERIVATIVES CONTAINING SULFA DRUG MOIETIES
© 2015 M. R. E. Aly* **, #, A. A. Gobouri*, S. H. Abdel Hafez*, ***, and H. A. Saad*, **** *Department of Chemistry, Faculty of Science, Taif University, Taif, 21974 Kingdom of Saudi Arabia **Department of Chemistry, Faculty of Applied Science, Port Said University, Port Said, Egypt
***Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt ****Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44511 Egypt Received August 8, 2014; in final form February 13, 2015
Thienyl-triazine-sulphonamide conjugates were prepared from their precursor amines using triethyl orthoformate or ethyl chloroformate as cross coupling reagents. The progress of these reactions was investigated by spectral (IR, NMR, MS) and microanalytical techniques. The synthesized compounds were in vitro screened for antibacterial, antifungal, antioxidant, and anticancer activity. 4-[({[3-Mercapto-5-oxo-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-4(5#)-yl]imino}methyl)amino]-benzenesulfonamide turned out to be a powerful antibacterial agent, while all the compounds prepared were inactive against fungal species tested. 4-{[({8-Cyano-4-oxo-3-[2-(2-thienyl)vinyl]-4^,8^-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-7-yl}amino)(ethoxy)methyl]amino}benzenesulfonamide displayed in vitro promising cytotoxicity against Ehrlich ascites carcinoma cell line with concurrent attenuation of malonod-initrile and it was unique among other compounds being unable to increase glutathione S-transferase and reduced glutathione S-transferase activities. This compound exhibited also good antioxidant properties that together with its cytotoxicity nominated it for further investigation in cancer research.
Keywords: 1,2,4-triazine, triazinothiadiazine, triazinecarbonitrile, sulfa drugs, biological activity. DOI: 10.7868/S013234231504003X
INTRODUCTION
Virulence of human microbial pathogens, cancer (as body dysfunction syndrome in consequence of mutations), and evolution of multidrug resistant species are posing serious global problems. Impairment of drug efficacy leads to prolonged therapy and even high mortality rates, particularly, in the case of epidemic disieses and cancer metastasis [1]. Mutant bacteria are stimulated to excrete P-lactamases that are able to detoxify P-lactam antibiotics. Clavulanic acid (I) and tazobactam (II) (Scheme 1) are co-administered to neutralize these resistance vectors [2].
Intrinsic fungal resistance, primary and secondary, is well documented in fighting mycosis. Upregulation of drug target fungal enzymes and activation of efflux systems are amongst the common fungal mechanisms to bypass the drug toxicity [3, 4]. Drug efflux proteins, for instance, P-glycoproteins are resistance vectors in several cancer species. Captopril (III) [5] is a commercial P-gp inhibitor co-administered with anticancer antibiot-
Abbreviations: BACE1 - Beta-secretase 1; DPPH - 2,2-diphe-nyl-1-picrylhydrazyl; EACC - Ehrlich ascites carcinoma cell line; GST - glutathione S-transferase; GST-Rd - reduced glutathione S-transferase; HIV - human immunodeficiency virus; MDR - multidrug resistance; P-gp - P-glycoproteins; SAR -structure—activity relationship; VEGFR - vascular endothelial growth factor receptor.
Corresponding author (e-mail: h_saadzag@yahoo.com).
ics to avert cancer resistance. Another complication in cancer therapy is the oxidative stress of many anticancer drugs. Drug candidates of dual antioxidant potency, therefore, are highly recommended [6].
Merging of specific pharmacophores in single architecture is a promising strategy to struggle against pathogens resistance. Sulphonamides, thiophenes, and 1,2,4-triazines are relevant multifunctional pharmacophores. Thus, sulphonamides reported mainly as antibacterial agents [7, 8], are also functioning as insulin releasing stimulants [9] and anti-inflammatory [10] and cytotoxic [11] agents.
1,2,4-Triazines documented as anti-HIV, anti-H5N1 virus agents [12—14] are also antiproleferative [15, 16] agents acting on VEGFR tyrosine kinases [17] as well as anti-tuberculosis [18], anti-anxiety, anti-inflammatory agents[19, 20], potent antidepression and antianxiety agents [21], and anti-breast cancer candidates [22]. Finally, thiophenes are well known as inhibitors of BACE1 preventing P-amyloid plaques formation in Alzheimer's disease [23, 24] and Plasomdium falciparum differentiation [25], anti-HIV [26], antiproleferative [27, 28], anti-inflammatory [29—31], antibacterial [32], and antiprotozoal [33] agents.
In continuation to our program on triazine chemistry [34—38], this article describes the design and synthesis of new thienyl-1,2,4-triazinyl sulphonamides as tripharma-
O.
%
Cl
ccooh H
V p^
■S > I N S
, O CH2OH H
(I)
NH2 N
O
O
OH
(II)
O O
O
VJ OH (III)
N NH2 MeO^^^ ^^OMe
(IV) (IV)
Scheme 1. Selected p-lactamase and P-gp inhibitors.
N
N
À " ^N sh
nh2
(VI)
R
x
O'" 'n^sh
rN
NH2
(IX)
h
I
R
O O
(Xa-e)
(VIIIa, Xa) (VIIIb, Xb) (VIIIc, Xc) (VIIId, Xd) (VIIIe, Xe)
R = H
N.
CH3CO
N
"O
Scheme 2. Reagents and conditions: (a) CH(OEt)3, AcOH, rfx. (92%); (b) AcOH, rfx. (64%).
a
cophoric probes for screening their latent antimicrobial, antioxidant, and antiproliferative potencies — the way that might lead to discovering new pharmacophore lead structures for application and optimization.
RESULTS AND DISCUSSION
Chemistry
In earlier attempts, 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4ff)-one (VI) [13] was activated as formamidate (VII) by refluxing with tri-ethyl orthoformate as cross coupling reagent in glacial acetic acid (Scheme 2). Compound (VII) showed 1H
NMR signals typical for ethyl group at 5 1.48 ppm, for CH3 as triplet, and at 5 4.52 ppm for CH2 as quartet. In 13C NMR spectrum, imine carbon was observed at 5 150.80 ppm. The IR spectrum was free from NH2 stretching vibration bands in the range 3300— 3100 cm-1.
Coupling of formamidate (VII) with available sulfa drug species (VIIIa-e) in refluxing AcOH led to transetherification of sulfa drugs yielding sul-fonamides (Xa-e) and unique imine (IX). 1H NMR spectrum of imine (IX) showed an NH2 signal at 5 6.46 ppm and a thiol signal at 5 14.00 ppm. This high downfield shift might be attributed to intramo-
(Xa) R = H
(Xb)
so2nhr
(Xc) (Xd)
( Xe)
CH3CO
Scheme 3. Plausible mechanism for the formation of compound (IX).
N
N
X
o N S
I /
-N H
r
VI + (VIIIa-e)
OEt
SO2NHR
( Xa-e)
(XIIa-c)
(XlIIa-c)
(VlIIa, Xla-XIIIa) (VIIIb, Xlb-XIIIb) (VIIIc, XIc-XIIIc) (VIIId, XIId) (VlIIe, XIIe)
R
H
N^
CH3CO
N
'O
Scheme 4. Reagents and conditions: CH(OEt)3, AcOH, Ac2O, rfx. (86% for (Xa); 74% for (Xb), and 68% for (Xc)).
a
lecular hydrogen bonding with the imine moiety in a five-membered ring structure. In 13C NMR spectrum, the imine carbon was observed at 6 154.00 ppm.
A plausible mechanism for this transetherification is described in Scheme 3.
Attempts to activate amines (VIIIa-e) by triethyl orthoformate followed by coupling with triazole (VI) were unsuccessful. Then, attention was given to three-component one-pot coupling of triazole (VI), amine (VIIIa-e), and CH(OEt)3 in AcOH containing several drops of Ac2O. Three target compounds (XIa-c) were successfully obtained (Scheme 4).
XH NMR spectra of target compounds (XIa-c) showed a number of N—H signals equivalent to those observed in corresponding structures along with the olefinic protons in s-trans configuration according to high vicinal coupling value, J ~ 16.2 Hz. The presence of S—H signal at 6 ~ 14.00 ppm excludes the bicylic structure (XIII) and the high chemical shift value supports structure (XI) instead of structure (XII) according to anticipated intramolecular hydrogen bond formation between the sulfohydryl group and the imine nitrogen in a five-membered ring structure, which is more favorable in structure (XI) than in structure (XII). The
NH2 and N—H stretching vibration bands in sulfonamide (XIa) were well distinguished and two N-H bands were also discriminated in case of derivatives (XIb) and (XIc). The C=O stretching bands were clearly seen in all conjugates and all these signals and bands gave supporting evidences for modular coupling of compound (VI) with sulfonamides (VIIIa-c).
Following the same procedure, compound (XIV) [38] was cross coupled with sulfonamides (VIIIa-c) affording conjugates (XVa-c) in excellent yields (Scheme 5).
\
N
N^ ^S^CN
N NH2
O
\
-N^/S. CN N V OEt r T
O
S- CNOEt
N^N-i i H H (XVa-c)
s; ,r
N i
H
R
(XVa) H
( XVb)
X)
( XVc)
Scheme 5. Reagents and conditions: (VIIIa-e), AcOH, Ac2O, rfx. (77% for (XI\k), 82% for (XIVb), and 92% for (XIVc)).
The IR spectrum showed two NH bands at 3240 and 3150 cm-1 along with disappearance of the NH2 band of precursor (XIV) reported at 3317 cm-1. The C=N stretching vibration band was observed around 2200 cm-1. The CH3CH2 signals in 1H NMR spectra appeared typically at 6 1.05-1.08 ppm for CH3 and 3.37-3.47 ppm for CH2. The SO2N-H signal was observed at 6 ~10.20 ppm. The 13C NMR spectrum supported the structure of compounds (XVa-c) through the appearance of signals at 6 ~59.9, 14.9, and 114.2 ppm arising from CH2, CH3, and C=N groups.
In a third attempt, compound (XVI) [39] was activated with CH(OEt)3 affording imidoformite (XVII) in good yield as described for the synthesis of compound (VII). The NH2 band at 3353 cm-1 disappeared upon activation and the appearance of CH3CH2 signals in 1H NMR at 6 1.88 and 3.88 ppm were good evidences for triazole (XVII). Compound (XVII) was successfully coupled with amines (VIIIa-c) and (VIIIe) in AcOH containing several drops of Ac2O to afford compounds (XVIIIa-c) andcompound (XVIIId) in very good yields (Scheme 6). IR spectra showed the number of NH2/NH stretching vibration bands corresponding to those in sulfonamides (XVIIIa-c) and (XVIIIe). The C=O stretching vibration bands
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