Synthesis and Biological Evaluation of Some 2-Mercaptobenzothiazole Derivatives

Mohamed Afzal, Azam (2011) Synthesis and Biological Evaluation of Some 2-Mercaptobenzothiazole Derivatives. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.


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Fast and effective relief of pain and inflammation in the human being is continued to be a major challenge for the medicinal chemistry researchers. Non-steroidal anti-inflammatory drugs (NSAIDs) are important therapeutic agents for the alleviation of pain and inflammation associated with a number of pathological conditions. However, chronic administration of NSAIDs has been associated with clinically significant complications such as gastrointestinal (GI) symptoms including mucosal damage, bleeding, nausea, heartburn, dyspepsia, abdominal pain and renal toxicity. Co-administration of multiple drugs for treatment of inflammatory conditions associated with microbial infection is a major risk especially in patients with prior history of peptic ulcer disease, patients with impaired liver or kidney functions and patients taking anticoagulants, corticosteroids, etc. concurrently. A mono therapy of a drug with dual antimicrobial and anti-inflammatory activity would be preferred from the pharmacoeconomic and patient compliance point of view. In view of the above-mentioned facts some novel 2-mercaptobenzothiazoles carrying 1,3,4-oxadiazole (ODZ1-15 and OXZ1-13), acetohydrazide (ACH1-5), 1,3,4-thiadiazole (TDZ1-13), 1,3,4-triazole (TRZ1-13) and 2-pyrazoline (PYZ1-19 and PYS1-9) moieties at the second position were synthesized. This combination was suggested in an attempt to develop hybrid compounds that would act as antimicrobial and analgesic-anti-inflammatory agents with minimal gastrointestinal (GI) side effects. The synthesized compounds were evaluated for their in vitro antimicrobial activity by the cup plate method. The tested compounds ODZ1-4, ODZ6, ODZ10, ODZ11 and ODZ13 showed significant inhibitory activity (inhibition zone 24-32 mm) against all the tested bacterial strains whereas compounds OXZ8, TRZ1, ATZ1, TDZ4, TDZ8, TDZ9, TDZ10, PYZ8, PYZ9, PYZ10 and PYZ14 indicated specific inhibitory activity (inhibition zone > 19 mm) against the Gram-negative bacteria Pseudomonas aeruginosa. In the present investigation tested compounds did not posses antifungal activity. Compounds that showed significant antibacterial activity were evaluated for their in vivo analgesic activity using tail immersion method in mice and results were compared with the reference standard drug paracetamol. In case of 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[5-(aryloxymethy)-1,3,4-oxadiazol-2-yl]acetamide the highest activity (76.5% analgesia) was observed at 3 h in derivative ODZ10. At first and second hour derivatives OXZ8 and OXZ11 belonging to the 2-{(benzo[d]thiazol-2-ylthio)methyl}-5-(aryloxymethyl)-1,3,4-oxadiazoles series and derivatives TDZ1 and TDZ9 belonging to the 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[5-(aryloxymethyl)-1,3,4-thiadiazol-2-yl]acetamide series exhibited significant analgesic activity (46.0-76.8%). Among 2-pyrazoline incorporated 2-mercaptobenzothiazoles, derivatives PYZ5, PYZ9, PYZ10 and PYZ14 exhibited potent analgesic activity (55.9 to 69.8%) at second and third hour following oral administration. Compounds were evaluated for their anti-inflammatory activity using the carrageenan induced paw oedema method in rats. At 2 and 3 h compounds ODZ4, ODZ6 and ODZ10 belonging to the 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[5-(aryloxymethy)-1,3,4-oxadiazol-2-yl]acetamide series were effective in inhibiting the paw oedema (58.2-68.2%), when compared with the reference drug diclofenac sodium. In case of 2-{(benzo[d]thiazol-2-ylthio)methyl}-5-(aryloxymethyl)-1,3,4-oxadiazole/triazole and 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[5-(aryloxymethyl)-1,3,4-thiadiazol-2-yl]acetamide series highest activity (81.6%) was found in derivative TDZ4 at 1h after carrageenan injection. Among the 2-pyrazoline incorporated 2-mercaptobenzothiazole analogs highest activity (76.9%) was observed at second hour in derivative PYZ14. On the other hand, sulfonyl analogs (PYS1-3) showed weak anti-inflammatory activity at all time interval. Compounds that exhibited higher analgesic and anti-inflammatory profiles in the prementioned animal models and promising antibacterial activities were further evaluated for their ulcerogenic potential. The results indicated low severity index of the tested compounds ODZ10, TDZ4, TDZ9, PYZ9 and PYZ14 ranging from 2.0±0.3 to 3.2±0.7.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Synthesis, Biological evaluation, 2-mercaptobenzothiazole.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Devi S
Date Deposited: 23 Jun 2017 06:28
Last Modified: 16 Sep 2022 03:03

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