Conversion of Benzimidazoles, Imidazothiazoles and Imidazoles into more Potent Central Nervous System Acting Drugs.

BACKGROUND: Benzimidazole (albendazole), imidazothiazole (levamisole) and imidazole (euconazole) are used in chemotherapy of helminthosis and mycosis respectively, with central nervous system (CNS) side effects. But only a limited number of azole groups are used clinically in the treatment of CNS diseases, which are on increase and could not be cured permanently. Due to increased incidence of more challenging new CNS diseases, there is a need for the synthesis of more potent CNS drugs. METHODS: Hence, literature studies were carried out for the identification of common pathways for the synthesis of the three groups of compounds, their CNS properties and the possibility of modifying them to potent CNS drugs. RESULTS: Findings have shown that gloxal with formaldehyde in the presence of ammonia can be converted into imidazole, imidazothiazole and benzimidazole via distillation, condensation, alkylation, acylation, oxidation, cyclization, sulphation and amidation. However, agents such as phosphorus pentoxide, ethanolic potassium hydroxide, sodium hypochlorite, sodium hexafluroaluminate, aniline, calcium acetate, calcium benzoate, sodium hydroxide, aromatic aldehydes, bromoketones, alpha dicarbonyl compounds among others are used as reagents. The furan ring(s) may have a strong capability of penetrating CNS for the treatment of neurological disorders. The products from the three groups have agonistic, antagonistic, mixed agonistic and mixed antagonistic depressant and stimulant activities due to the presence of heteroatoms such as nitrogen, oxygen and sulphur. Imidazole may be the most potent with best characteristics of CNS penetrability and activity followed by imidazothiazole and benzimidazole. CONCLUSION: Azole group is common to all the three classes and may be responsible for some of their CNS effects. The resultant compounds could act via all neurotransmitters, voltage and ligand-gated ion channels and may be chiral.

Biomedical Application of Polymers: A Case Study of Non-CNS Drugs Becoming CNS Acting Drugs.

BACKGROUND: The transport of CNS acting drugs across blood-brain barrier (BBB) is complex and guided by the molecular weight, pH, physicochemical and pathological state of the BBB among others. METHODS: In view of this, literatures were assessed for possible conversion of Non-CNS to CNS acting drugs, whose ability to penetrate CNS can be improved using polymers for biomedical applications. RESULTS: The findings have shown that compounds with pyridine, pyrrole, carboxamide, pyridone among others can be converted to CNS acting drugs that can be loaded in specialized carrier polymers for transportation across BBB. Such carriers are polymers, co-polymers, nanopolymers and polymeric miscelles that have amine around and pyridine as their hydrophobic site and carboxylic acid as their hydrophilic site. But balanced hydrophilic/hydrophobic site (amphiphilic) may not increase the transport rate of the carrier molecule. CONCLUSION: Polymeric nanoparticles and copolymers can be used. Examples of such polymers are poly (lactic-co-glycolic acid), polylactic and poly (propyleneglycol, poly (DI)-lactide, polycaprolactone, and polyethylene glycol (hydrophilic). They are non-soluble, biodegradable, release the entrapped drug as they degrade via passive diffusion from polymeric core. Some of their degradation products can be converted to glycolic acid and lactic acid which are converted to carbon dioxide and water through the Kreb's cycle and finally eliminated via urination, perspiration, defecation and expiration.

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

INTRODUCTION: Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. METHODS: The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. RESULTS AND CONCLUSION: Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome.

In vivo Piroxicam Metabolites: Possible Source for Synthesis of Central Nervous System (CNS) Acting Depressants.

BACKGROUND: Piroxicam has been reported to be convertible to Central Nervous System (CNS) acting agents. It has serious depressant effects at high doses. OBJECTIVE: In view of this, structures of piroxicam metabolites were assessed for possible conversion to CNS depressants. METHODS: Literature search was carried out with intent to identifying piroxicam metabolites and the possibility of converting them to CNS acting depressants. RESULTS: Piroxicam is convertible to hydroxymethylated metabolite which may be converted to barbiturates such as thiopentone and thiamylal. Whereas cyclodehydrated metabolite may be converted to acetylcyclodehydrated compound that may be in turn converted to acetylacetone and cyclohexamide. However, carboxybenzothiazine metabolite may be converted to carboxamide compound, benzolactone which is convertible to phenazone. Carboxybenzothiazine is also convertible to 2-aminopyridine mepyramine and triplenamine. Conversion of carboxybenzothiazine to gamma aminobutyric acid and phenothiazines such as chlorpromazine, thioridazine, fluphenazine and perphenazine is highly possible. CONCLUSION: Structurally, barbituric compounds, carboxamide, cyclodehydrated, benzothiazine and carboxybenzothiazine metabolites may act via dopamine and adrenergic receptors causing depression of CNS activities. Piroxicam metabolites may also act via histamine, melatonin and potassium channel receptors causing CNS depression.