ABSTRACT
We have synthesised a series of 2-[[2-alkoxy-6-pentadecylphenyl)methyl]thio]-1H-benzimidazoles/benzothiazoles and benzoxazoles from anacardic acid and investigated their ability to inhibit human cyclooxygenase-2 enzyme (COX-2). The active compounds were screened for cyclooxygenase-1 (COX-1) inhibition. Compound 13 is 384-fold and 19 is more than 470-fold selective towards COX-2 compared to COX-1. Thus, this class of compounds may serve as excellent candidates for selective COX-2 inhibition.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Benzothiazoles , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacology , Blood/metabolism , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Membrane Proteins , Prostaglandin-Endoperoxide Synthases , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Anacardic acid (6-pentadecylsalicylic acid), a major component of cashew nut shell liquid, consists of a heterogeneous mixture of monoenes, dienes, and trienes. The enes mixture of anacardic acid was hydrogenated to a saturated compound. Using saturated anacardic acid as a starting material, analogues of sildenafil [a potent phosphodiesterase-5 (PDE(5)) inhibitor and an orally active drug for the treatment of erectile dysfunction] were synthesized, to observe the effect of the pentadecyl side chain on PDE(5) inhibition. The synthesized compounds were characterized by spectral studies and tested for PDE(5) inhibition, and the results were compared with those obtained with sildenafil.
Subject(s)
Anacardic Acids , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Piperazines/chemistry , Salicylates/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases , Cyclic Nucleotide Phosphodiesterases, Type 5 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Phosphoric Diester Hydrolases/metabolism , Piperazines/pharmacology , Purines , Sildenafil Citrate , Structure-Activity Relationship , SulfonesABSTRACT
Commercially available technical cashew (Anacardium occidentale L.) nut shell liquid (CNSL) contains mainly cardanol (decarboxylated anacardic acid) and cardol. Cardanol, the monophenolic component of technical CNSL, is widely used as a synthon for the preparation of a number of polymers and agricultural products. This paper describes the separation of cardanol from toxic cardol. Technical CNSL was dissolved in a mixture of methanol and ammonium hydroxide (8:5) and extracted with hexane to obtain cardanol. The resultant methanolic ammonia layer was extracted with a mixture of ethyl acetate and hexane to yield cardol. This is the first industrially feasible process based on solvent extractions for the isolation of cardanol from technical CNSL.
Subject(s)
Anacardiaceae/chemistry , Nuts/chemistry , Phenols/isolation & purification , Acetates , Ammonium Hydroxide , Chromatography, High Pressure Liquid , Hexanes , Hydroxides , Magnetic Resonance Spectroscopy , Methanol , Resorcinols/isolation & purification , SolventsABSTRACT
We have synthesized a novel series of 18 dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates from anacardic acid, a natural compound found in cashew nut shells, and investigated their blocking action on L- and T-type calcium channels transiently expressed in tSA-201 cells. The IC(50) values for L-type calcium channel block obtained with the series ranged from 1 to approximately 40 microM, with higher affinities being favored by increasing the size of the alkoxy group on the 4-phenyl ring and ester substituent in the 3,5 positions. A detailed analysis of the strongest L-type channel blocker of the series (PPK-12) revealed that block was poorly reversible and mediated an apparent speeding of the time course of inactivation. Moreover, in the presence of PPK-12, the midpoint of the steady state inactivation curve was shifted by 20 mV toward more hyperpolarized potentials, resulting in an increase in blocking efficacy at more depolarized holding potentials. Surprisingly, PPK-12 blocked T- and L-type calcium channels with similar affinities. One of the weakest L-type channel inhibitors (PPK-5) exhibited a T-type channel affinity that was similar to that seen with PPK-12, resulting in a 40-fold selectivity of PPK-5 for T- over L-type channels. Thus, dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates may serve as excellent candidates for the development of T-type calcium-channel specific blockers.
Subject(s)
Calcium Channel Blockers/chemical synthesis , Calcium Channels, T-Type/metabolism , Nifedipine/chemical synthesis , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/drug effects , Cells, Cultured , Electrophysiology , Humans , Nifedipine/analogs & derivatives , Nifedipine/chemistry , Nifedipine/pharmacology , Structure-Activity Relationship , TransfectionABSTRACT
Commercially available cashew (Anacardium occidentale L.) nut shell liquid (CNSL) mainly contains the phenolic constituents anacardic acid, cardol, and cardanol. These phenolic constituents are themselves heterogeneous, and each of them contains saturated, monoene, diene, and trienes in the fifteen-carbon side chain. This communication describes the separation of anacardic acid, cardol, and cardanol for industrial application. Anacardic acid was selectively isolated as calcium anacardate. The acid-free CNSL was treated with liquor ammonia and extracted with hexane/ethyl acetate (98:2) to separate the mono phenolic component, cardanol. Subsequently, ammonia solution was extracted with ethyl acetate/hexane (80:20) to obtain cardol.
