Substituted Aminobenzothiazole Derivatives of Tacrine: Synthesis and Study on Learning and Memory Impairment in Scopolamine-Induced Model of Amnesia in Rat.

BACKGROUND: Currently, there is no conclusive cure for Alzheimer's disease (AD) and existing treatments mainly offer symptomatic relief. Dysfunction of the cholinergic system plays an important role in the pathogenesis of AD. Tacrine (1, 2, 3, 4-tetrahydroacridin-9-amine, III) was the first approved agent for the palliative therapy of AD but its use is associated with some complications. Development of novel multi target derivatives of Tacrine with lower complications is strongly warranted. In this study, new aminobenzothiazole (1-5, with many useful biological and pharmacological properties) analogues (IV-VIII) were synthesized by changing of amine moiety of III. Then, the effects of these new compounds on learning and memory impairment in scopolamine-induced model of amnesia were studied and the outcomes were compared with control and Tacrine groups in rat. MATERIAL AND METHODS: The rats received Tacrine or its derivatives (IV-VIII) i.p. for two weeks at a dose of 10 mg/kg. For induction of amnesia, scopolamine at a dose of 1 mg/kg was daily administered i.p. started on day-8 till the end of the study. Behavioral experiments including Y-maze, novel object recognition (discrimination) and passive avoidance paradigms were conducted at week 2. RESULTS: Data analysis showed that some Tacrine derivatives, especially VII with 2-amino, 6-nitrobenzothiazole moiety, could markedly and significantly improve alternation score, discrimination ratio and step through latency compared to control and Tacrine groups. CONCLUSION: These findings indicated that some of these derivatives (especially compounds VI and VII) are capable to mitigate learning and memory deficits in scopolamine-induced model of amnesia in rats and may have potential benefit in management of patients with AD.

Synthesis and Antinociception Activities of Some Novel Derivatives of Phencyclidine with Substituted Aminobenzothiazoles.

BACKGROUND: Phencyclidine (PCP) as well as the analogues has indicated several pharmacological behaviors like analgesic, anticonvulsant, antianxiety, antidepressant depending on the dose and species examined. They interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or both. OBJECTIVE: Due to analgesic properties of aminobenzothiazoles family, piperidine ring of PCP was replaced with electron-donating and electron-withdrawing substituted aminobenzothiazoles (1-4) for obtaining new analogues (II-V) with more analgesic activities. METHODS: Synthesis of new compounds (II-V) and measuring the acute and chronic pain properties of them were carried out through applying tail immersion &formalin tests on mice and the outcomes compared with control & PCP groups at dosage of 10 mg/kg. RESULTS: III & V with substituted methoxy and methyl-aminobenzothiazoles indicated better activity to lessen acute and chronic (thermal and chemical) pains compared with unsubstituted & phencyclidine animal groups. CONCLUSION: Methoxy and methyl-aminobenzothiazole derivatives" of phencyclidine revealed more analgesic activities compared with other groups which may concern to close affinity for DA uptake blocking as well as NMDA receptors in this family.

Synthesis and Study of Analgesic and Anti-inflammatory Activities of Amide Derivatives of Ibuprofen.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide and represent a mainstay in the therapy of acute and chronic pain and inflammation. The traditional NSAIDs like ibuprofen (I) contain free carboxylic acid group which can produce gastrointestinal (GI) damage for long-term use. OBJECTIVE: In order to obtain the novel NSAIDs with less side effects; carboxylic acid moiety has been modified into various amide groups which is the most active area of research in this family. METHOD: In this research, synthesis of various pharmacological heterocyclic amides of ibuprofen is described. All the new compounds were tested for their analgesic and anti-inflammatory activities in mice and compared with standard (Ibuprofen) and control (saline) groups. RESULTS & CONCLUSION: The results revealed that all the synthesized compounds (III-VI) exhibited more analgesic and anti-inflammatory activities in tail immersion (as a model of acute thermal pain), formalin (as a model of acute chemical and chronic pain) and paw edema (as a model of acute inflammation) tests when compared with standard and control animals. These pharmacological activities were significant for VI compared to other new compounds (III-V) which may be concern to more effective role of morpholin for the reduction of pain and inflammation compared to other used heterocyclic amines.

Synthesis and Evaluation of the Hypoglycemic and Hypolipidemic Activity of Sulfonamide-benzothiazole Derivatives of Benzylidene-2,4- thiazolidnedione.

BACKGROUND: Thiazolidinediones (TZDs) and sulfonamides are important and highly consumption class of antidiabetic drugs having insulin sensitizing and stimulating properties in patients with type 2 diabetes, respectively. OBJECTIVE: In this paper, some novel benzothiazole derivatives of TZD-sulfonamides were synthesized (I-IV) and evaluated for anti-hyperglycemic and anti-hyperlipidemic activities in the STZ-induced diabetic rat model. RESULTS: Results indicated that all new conjugated compounds showed significant hypoglycemic activities compared to control animals that were better for I and IV than others. Moreover, these new compounds displayed high efficiency for lowering lipid profiles as compared to control and standard (Pioglitazone) groups that was significant and higher for I than others. CONCLUSION: It is concluded that these new conjugated TZD-sulfonamide-benzothiazoles (I-IV) can indicate useful results for hypoglycemic and hypolipidemic activities compared to control and standard groups, respectively with different mechanism that is closer to TZDs' analogs.

Synthesis and Analgesic Properties of Lidocaine Derivatives with Substituted Aminobenzothiazoles.

Local anesthetics are the most widely consumed drugs in the practice of medicine which provide a loss of sensation in a certain body part without loss of consciousness or impairment of central control of essential functions. Lidocaine (I) is the most commonly local anaesthetic drug which is widely used in all species due to its fabulous diffusing and penetrating properties as well as prompt onset of surgical analgesia. In this study, new aminobenzothiazole (with many useful biological and pharmacological properties) analogues were synthesized by changing of amine moiety of I. Both acute and chronic pain properties of new compounds (II-VI) were studied by using the tail immersion and formalin tests on mice and the outcomes were compared with control and lidocaine groups. According to the results, aminobenzothiazole derivatives are better candidates than diethylamine group for replacement on amine moiety of I. Also, derivatives with electron-withdrawing groups on this amine (V and VI) could decrease pain better than electron-donating ones (II and III) (specially on position 6 of this amine, II and V) which may be of concern for blockade of specific sodium channels by these new compounds.

Synthesis and investigating hypoglycemic and hypolipidemic activities of some glibenclamide analogues in rats.

Glibenclamide (5-chloro-N-(4-[N-(cyclohexylcarbamoyl) sulfamoyl] phenethyl)-2-methoxybenzamide, Glyburide, E) is a well-known and potent second-generation of sulfonylurea oral hypoglycemic drug which is most widely used in type 2 diabetes recently. It acts upon pancreatic ß-cells by stimulating insulin secretion in glucose and lipid-lowering activities. So far, many derivatives of E have been synthesized by adding new structural moieties to its structure while preserving its binding affinity to the receptor before their anti-hyperglycemic and anti hyperlipidemic activities being evaluated. In this study, new analogues of E after changing lipophilic side chain (5-chloro-2-methoxy benzamide) with 4- bromo-3, 5-dimethoxy benzamide and 2, 4-dichloro benzamide were synthesized. Also, their glucose and lipid-lowering activities were evaluated and compared to E and Tolbutamide (a famous first-generation of sulfonylurea oral hypoglycemic drug) by the known procedures. Findings showed that chloride substitution on lipophilic side chain of Glibenclamide could possibly increase the affinity of drug for receptor/or its half life time that resulted in more lasting anti-hyperglycemic and anti lipidemic activities in diabetic rats. However, bromide substitution with additional methoxy groups in benzamide ring could slightly improve the anti-hyperglycemic potency of the new drug compared to the root drug (E).

Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice.

Phencyclidine (PCP, I) and many of its derivatives have demonstrated many pharmacological effects. They interact with a number of neurotransmitter systems within the central nervous system. For example, Phencyclidine is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor, and it causes the release and inhibits the reuptake of monoaminergic neurotransmitters, including dopamine, serotonin and norepinephrine. In this study, new thienyl (TCP, II), as well as benzothiophen (BTCP, III) derivatives (IV-VII) were synthesized. The acute and chronic pain activities of these drugs were studied using the tail immersion and formalin tests on mice and the results were compared with PCP, TCP and control groups at dosage of 10 mg/kg. The results indicated that the drug VII produced more analgesic effects on acute chemical pain in formalin test compared with other drugs. In addition, this analgesic effect was remarkably seen for drugs II, VI and VII in chronic pain in the mentioned test in comparison with other drugs. Also, the results showed that acute thermal pain could be diminished by drugs VI, II and I compared with other drugs in tail immersion test. It can be concluded that more analgesic effects of new BTCP analogues (VI and VII) may be concerned with antinociception activities of benzothiophene group and also with binding to cocaine site on the dopamine transporter receptor which seems to be more potent than PCP receptor in decreasing pain.

Synthesis and anti-inflammatory effects of new piperazine and ethanolamine derivatives of H(1)-antihistaminic drugs.

In addition to their antihistamine effects, H1-receptor antagonists possess pharmacological properties that are not uniformly distributed among this class of drugs, such as anti-inflammatory, anti-allergic and antiplatelet activities. In this paper, Cyclizine (1-benzhydryl-4-methyl-piperazine, I), bromodiphenhydramine (2-[(4-bromophenyl)-phenylmethoxy]-N, N-dimethylethanamine, II) and some of their new piperazine and ethanolamine derivatives (III-VIII) inducing changes in substitution of phenyl and amine moieties were synthesized and their acute and chronic antiinflammatory effects were evaluated by standard pharmacological tests. The results showed that substitution of phenyl by tolyl, anisol and cumene groups in piperazine family could remarkably decrease acute inflammation in these new drugs. Also, substitution of dimethylamine by morpholine group could not decrease this inflammation in new synthesized ethanolamine family. But the results from the cotton pellet-induced granuloma formation in rats showed that none of drugs (I-VIII) were effective to reduce the chronic inflammation.

Synthesis, antidiabetic and hypolipidemic activities of new diethylamine and triethoxysilyl derivatives of tolbutamide on rats.

Tolbutamide (N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide, CAS 64-77-7, I) is the first generation of potassium channel blocker and sulfonylurea oral hypoglycemic drug that imparts marked blood glucose lowering effect in type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM) patients. In this study, I and its two new analogs with substituting butylamine side by 3-diethylamino-1-propylamine (3) and 3-triethoxysilyl-1-propylamine (4) were synthesized and their antidiabetic and hypolipidemic activities were evaluated applying known procedures, and compared with both I and glibenclamide (II, well known second-generation sulfonylurea antidiabetic drug). The results showed that these new drugs (III and IV) were more potent than I and II and it could be concluded that changing the amine side of I would produce more potentials in new drugs (III and IV) of the first generation, to be named as the third generation. Also investigations on hypoglycemic and lipid lowering effects of these drugs proved that IV could reduce glucose, triglyceride (TG) and a low density lipoprotein (VLDL) level in blood serum more than others (I-III), 16 days after STZ injection.

Synthesis and study the analgesic effects of new analogues of ketamine on female wistar rats.

Ketamine (2-o-chlorophenyl-2-methylaminocyclohexan, CAS 1867-66-9, CI-581, Ketalar, I), a potent derivative of Phencyclidine (1-[1-phenylcyclohexyl] piperidine, CAS 956-90-1, PCP, II), and many of its analogues have shown anesthetic and analgesic effects. In this research, new derivatives of I, (2-[p-methoxybenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-OCH3, III), (2-[p-methylbenzylamino]-2-[p-methoxyphenyl] cyclohexanone, ket-CH3, IV) and their intermediates (V-VIIII) were synthesized and the acute and chronic pains of III and IV were evaluated on rats using tail immersion (as a model of acute thermal pain) and formalin (as a model of acute and chronic chemical pain) tests. The results werecompared with ketamine and control (saline) groups. The results indicated that in tail immersion and formalin tests, these new derivatives (III and IV) were usually effective for decreasing pain on rats.

Synthesis and Anti-inflammatory Performance of Newly Cyclizine Derivatives on Adult Male Wistar Rats.

Cyclizine (1-benzhydryl-4-methyl-piperazine, CAS 82-92-8, CYC, I), a piperazine derivative, belongs to H1 antihistamine group of drugs that shows such pharmacological properties as anti-inflammatory, anti-allergic and anti-platelet effects, similar to other H1-receptor antagonists. In this study, two new tolyl and cumene derivatives of I (1-ethyl- 4-[(p-isopropylphenyl) (p-tolyl) methyl]-piperazine, II and 1-[3, 4-dichlorophenyl]-4-[[p-isopropylphenyl] [p-tolyl] methyl]-piperazine, III) were synthesized to investigate their acute and chronic anti-inflammatory activities in formalin and histamine-induced rat paw edema. In addition, the vascular permeability in formalin and histamine-induced paw edema, xylene-induced ear edema, and peritonitis due to acetic acid application into peritoneal cavity were measured. The cotton pellet-induced granuloma model was chosen for inducing chronic inflammation in rats. Findings proved reduction in formalin-induced rat paw edema and vascular permeability (acute inflammation) by I and II at 30 min after the injection. In addition, results in histamine-induced rat paw edema showed anti-inflammatory effects of all drugs started 60 min after the injection as these effects continued for a longer period by II and III comparing to I, as discussed above. In addition, the data on vascular permeability in xylene-induced ear edema and acetic acid-induced to peritoneal cavity confirmed that substitutions on cyclizine molecule were more effective and could decrease the vascular permeability and acute inflammation. However, the results from the cotton pellet-induced granuloma formation in rats revealed that none of the drugs (I-III) were effective to reduce the reactions and intermediates of chronic inflammation.