EHOOPrAHH^ECKAa XHMH3, 2015, moM 41, № 2, c. 249-256
SYNTHESIS AND BIOLOGICAL EVALUATION OF ^-(SUBSTITUTED PHENYL)-2-(5#-[1,2,4]TRIAZINO[5,6-4]INDOL-3-YLSULFANYL)ACETAMIDES AS ANTIMICROBIAL, ANTIDEPRESSANT
AND ANTICONVULSANT AGENTS
© 2015 N. Shruthi", Boja Poojary", *, Vasantha Kumar", A. Prathibha", Mumtaz Mohammed Hussain4, B. C. Revanasiddappac, and Himanshu Joshic
aDepartment of Chemistry, Mangalore University, Mangalagangothri-574199, Karnataka, India bDepartment of Pharmaceutical Chemistry, S.J.M. College of Pharmacy, Chitradurga-575501, Karnataka, India cDepartment of Pharmacology, N.G.S.M. Institute of Pharmaceutical Sciences, Paneer, Deralakatte, Mangalore-575 018, Karnataka, India Received September 8, 2014; in final form, November 3, 2014
A new series of N-Aryl-2-(5#-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides were synthesized by condensation of tricyclic compound 2,5-dihydro-3#-[1,2,4]triazino[5,6-b]indole-3-thione with chloro N-phe-nylacetamides. The tricyclic compound was obtained by condensation of Isatin with thiosemicarbazide. Chloro N-phenylacetamides were obtained from different substituted anilines. Their structures were characterized by IR, 1H NMR, LC-MS and elemental analyses. Newly synthesized compounds were screened for antimicrobial, antidepressant and anticonvulsant activities. Preliminary results indicated that most of the compounds showed lesser MIC value than the standard drug used when tested for antimicrobial activity. Some of the compounds were endowed with very good antidepressant and anticonvulsant activity.
Keywords: [1,2,4]triazino[5,6-b]indoles, antimicrobial activities, antidepressant activities, anticonvulsant activities. DOI: 10.7868/S0132342315020141
Most of the antidepressants exert its actions on the metabolism of monoamine neurotransmitters particularly on nor-adrenaline and serotonin . They are effective and tolerated well, but noncompliance due to the slow action, low response and a plethora of side effects are generally observed [2—7]. Also, they inhibit sexual behavior . Epilepsy is another common neurological disorder characterized by unprovoked seizures. Phenobarbital and mephobarbital are well-known drugs used for the treatment of epilepsy . Available antiepileptic drugs are effective in controlling seizures of only about 70—80% of patients. But they suffer from major side effects like sedation and hypnosis along with drowsiness, ataxia, gastrointestinal disturbance, hepatotoxicity and megaloblastic anemia and even life-threatening conditions [10, 11]. Hence, there is a continuing demand for the new anti-convulsant and antidepressant agents as it has not been possible to control the side effects by currently available drugs. Heterocyclic nucleus imparts an important role in the field of medicinal chemistry and serves as a key template for the development of various bioactive molecules. The triazino[5,6-b]indole derivatives have
1 Corresponding author (tel./fax: +91-824-2287262/2287367, e-mail: email@example.com).
aroused considerable interest as a result of their high potential of biological activities such as antibacterial, antifungal , antihypertensive , antimalarial , antihypoxic , antiparasitic  and antidepres-sant  activities. Importantly, this tricyclic structure is comparable to P-carboline (9H-pyrido[3,4-b]indole), an endogenous monoamine oxidase inhibitor . The majority of the 5#-as-triazino[5,6-b] indoles are active in vitro against a variety ofviruses including several strains of rhinovirus . They are used in the prophylaxis and treatment of an extensive index of viruses and have for a long time attracted attention in connection with the search for new antimicrobial and anticancer agents [20, 21]. For a search of effective small molecules with promising biological activity, it was envisaged to synthesize a series of N-(substituted phenyl)-2-(5#-[1,2,4] triazino [5,6-b] indol-3-ylsulfanyl)acetamide derivatives.
RESULTS AND DISCUSSIONS
In our present work, tricyclic compound 1,2,4-tri-azino[5,6-b]indole-3-thione (II) was prepared by referring previously reported literature procedure . Isatin (I) was condensed with thiosemicarbazide in aqueous solution of potassium carbonate. Obtained clear solution was acidified with glacial acetic acid to afford the condensed product (II). Different chloro
^-phenylacetamides (III) was prepared as per the literature procedure  involving the reaction of primary amines with chloro acetyl chloride in glacial acetic acid in the presence of saturated solution of sodium acetate. The title compounds (IVa)-(IVq) were accomplished by overnight stirring of tricyclic
product (II) with appropriate chloro ^-phenylaceta-mides (III) in dry DMSO containing anhydrous milled potassium carbonate. The synthetic route is depicted in Scheme. Synthesized compounds were characterized by IR, XH NMR, LC-MS and elemental analyses.
O + NHj^N—NH2"
2 H 2
g lacetic acid
Cl CH3COONa R |
/TX NN n
C6H4; b: R = 2-CF3
a: R = 3-CN c: R = 2-CNC6H4; d: R e: R = 4-Br-2-pyridinyl; f: R
3-CF3C6H4; h: R = 4-OCF3
i: R = 4-CN-2-pyridinyl; j: R = k: R = 2,4,5-Cl3C6H2; l: R = m: R = benzothiazolyl; n: R = 2,5-Cl2—C6H3; o: R = 2-Cl-6-CH3-pyridinyl; p: R = 2,4-F2-C6H3; q: R = 5-CH3-2-pyridinyl
= 3,5-Cl2-C6H3; 3-Cl-4-F-C6H3;
Scheme 1. Synthetic route for the compounds (IVa)—(IVq).
IR spectrum of prototype compound (IVa) showed prominent absorption bands corresponding to N—H stretching of secondary amide near 3323 cm-1 and an amide carbonyl at 1670 cm-1. Presence of aromatic skeleton is confirmed by peak at 3057 cm-1 corresponding to aromatic C—H stretching. 1H NMR of (IVa) displayed singlet at 5 4.28 for methylene protons alpha to carbonyl group. Presence of two doublets and two triplets confirmed the presence of triazino indole moiety. A singlet at 5 8.08 and Multiplet at 5 7.47-7.57 integrating for one and three aromatic protons respectively affirmed the presence of 3-cyanophenyl ring in the title compound. Further, broad singlet at 5 10.74 revealed the presence of an amide NH proton. The downfield broad singlet at 5 12.52 corresponds to indole NH proton. Formation of the compound is further confirmed by the presence of M+ and M + 2 peaks at m/z values 360 and 362 respectively.
The newly synthesized compounds (IVi)-(IVq) were screened for in vitro antimicrobial activity (mini-
mum inhibitory concentration) against Gram positive bacterial strains Stephylococcus aureus, Enterococcus faecalis, Gram negative bacterial strains Escherichia coli, Klebsiella pneumonia and two fungal strains As-pergillus niger and Candida albicans by Tube Dilution Method. Results of antimicrobial study are shown in Table 1 and Table 2. Antibacterial studies revealed that most of the compounds have shown good inhibition against gram positive bacterial strains when compared with reference drug used, Ciprofloxacin (MIC : 2 ^g/mL against S. aureus and MIC : 1.0 ^g/mL against E. feacalis). Compounds (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVh), (IVi), (IVj), (IVk), (IVl), (IVn), (IVo), (IVp) have shown more inhibition against gram positive bacterial strains as compared to Ciprofloxacin where as compounds (IVg), (IVm) and (IVg) found to be less effective. Against gram negative bacterial strains, compounds (IVe) and (IVi) were showed good inhibition than standard drug used; whereas rests of the compounds were shown weak inhibition. From structural activity relationship it was clear that
Table 1. MIC values of in vitro antibacterial study for the analogs (IVa)-(IVj)
Compound MIC values ( ^g/mL)
Gram positive Gram negative
Staphylococcus aureus Enterococcus faecalis Escherichia coli Klebsiella
(IVa) 0.4 0.4 6.25 12.5
(IVb) 0.8 0.8 12.5 6.25
(IVc) 0.4 0.2 3.12 3.12
(IVd) 0.2 0.2 3.12 1.6
(IVe) 0.4 0.8 0.2 0.8
(IVf) 0.4 0.8 3.12 6.25
(IVg) 12.5 6.25 3.12 12.5
(IVh) 0.8 0.4 3.12 12.5
(IVi) 0.2 0.2 0.2 0.2
(IVj) 0.4 0.2 6.25 6.25
(IVk) 0.2 0.2 12.. 25
(IVl) 0.2 0.2 12.5 6.25
(IVm) 12.. 6.5 25 25
(IVn) 0.8 3.12 25 12.5
(IVo) 0. 0. 50 25
(IVp) 0.. 1.. 50 12..
(IVq) 6.25 6.25 50 25
Ciprofloxacin 2.0 1.0 2.0 1.0
electron withdrawing group and heterocyclic substituted compounds have shown good inhibition against S. aureus and E. faecalis bacterial strains. Against E. coli and K. pneumonia, Halo-pyridine substituted derivatives were found to be potent inhibitors.
The reference drug Flucanazole is selected as positive control for antifungal activity assay. All the compounds have shown excellent inhibition (MIC < 16 ^g/mL) against C. albicans when compared with standard drug Flucanozole (MIC: 16 ^g/mL). Against A. niger, except (IVg) and (IVm) rest of the compounds showed MIC value less than standard used (MIC: 8 ^g/mL). It was observed that all the compounds are potent against C. albicans and A. niger, except electron donating het-erocyclic substituted derivatives against A. niger when compared with Flucanazole.
Antidepressant activity of the synthesized compounds (IVa)-(IVq) was done by using tail suspension test. This test is effectively used to predict the activity of a wide variety of antidepressants such as Mao inhibitors. During the pharmacological evaluation, only a few of the synthesized compounds exhibited moderate antidepressant activity in the tail suspension test, with many exhibiting weak activity as shown in Table 3. However, in the series, mono and dihalo substituted derivatives showed a favorable influence on the activity as seen in the compounds (IVd), (IVj), (IVk), (IVl), (IVn) and (IVp). Among the tested compounds, 4-F
Table 2. Results of in vitro antifungal activity for the compounds (IVa)-(IVq)
Compound MIC values ( ^g/mL)
Aspergillus niger Candida albicans
(IVa) 0.. 0..
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