ABSTRACT
In the framework of pursuing the design and synthesis of a new series of substituted 6-methoxybenzothiazole-2-carbamates as potential anthelmintics, and as a continuation of the expended efforts in part I, we have set out to develop novel compounds with enhanced anthelmintic activity by blocking the 6-position of benzothiazole with side chains of different polarities. Guided by the findings in part I, and reporting the paramphistomicidal activity of oxadiazoline derivatives V and VI, we aimed to synthesize target benzothiazoles designed to comprise some planar heterocyclic ring systems, namely, 1,3,4-oxadiazoles and 1,2,4-triazoles, bearing a variety of hydrophobic and hydrophilic components. The synthesis of the desired compounds was primarily achieved by cyclization of 6-acetohydrazide, 1. The in vitro paramphistomicidal activity of all synthesized carbamates was evaluated. Four synthesized carbamates exhibited notable activity. Compound 24, methyl 6-[(5-(4-bromophenacylsulfanyl)-[1,3,4]-oxadiazol-2-yl)methoxy]benzothiazole-2-carbamate, displayed an equipotent effect to the reference drug oxyclozanide at a concentration of 80 µg mL-1; compounds 9, 10 and 23 showed high orders of anthelmintic effect. A structural computational study on the polar nature and hydrophilic-lipophilic properties of the synthesized carbamates was undertaken to discuss their structure-activity relationship (SAR). Besides, pharmacophore mapping was performed using eight active compounds as a training set. The generated pharmacophore model revealed five common features and was validated using fenbendazole, triclabendazole and triclabendazole sulfoxide.
ABSTRACT
INTRODUCTION: In China, Wuling capsule, a traditional Chinese medicine consisting of Wuling mycelia of Xylaria nigripes (Kl.) Sacc (a rare type of fungus), is used to treat major depressive disorders. A meta-analysis of randomised controlled trials was performed to compare the efficacy and safety of Wuling capsule alone with Wuling capsule-antidepressant combination in the treatment of major depressive disorders. METHODS: Two assessors independently selected studies, extracted data, and conducted quality assessment and data synthesis. Standard mean difference, risk ratio (RR) ± 95% confidence interval (CI), the number needed to treat, and the number needed to harm were analysed. RESULTS: A total of 12 randomised controlled trials (880 patients; mean age ± standard deviation, 39.7 ± 12.5 years; male patients, 41%) were identified, including 4 trials with Wuling capsule alone (n = 340) and 8 with Wuling capsule-antidepressant (sertraline, mianserin, mirtazapine, and paroxetine) combination (n = 540). The mean length of trial was 5.7 ± 1.3 weeks. Meta-analysis of symptomatic improvement at last-observation endpoint and study-defined response and remission revealed no significant differences between the Wuling capsule alone and antidepressant monotherapy. The Wuling capsule-antidepressant cotreatment was superior to antidepressant monotherapy in symptomatic improvement at last-observation endpoint (standard mean difference: -0.46, p = 0.001) as well as study-defined response (68.4% vs. 56.0%, RR = 1.23; p = 0.03) and remission (46.5% vs. 34.5%, RR = 1.35; p = 0.05). Wuling capsule was associated with fewer adverse drug reactions than antidepressant monotherapy. CONCLUSIONS: Adjunctive Wuling capsule may augment the effects of antidepressants and may be associated with fewer adverse drug reactions. More large-scale and rigorously designed randomised controlled trials with large sample size are warranted to clarify the effectiveness of Wuling capsule for major depressive disorders.
