ABSTRACT
The intramolecular Diels-Alder reaction (IMDA) of a butenolide derivative, as an entry to the type II abyssomicin scaffold, and the total synthesis of (±)-abyssomicin 2 and (±)-neoabyssomicin B are reported for the first time. A facile route to the IMDA precursor, the formation of a type I intermediate and two paths to (±)-neoabyssomicin B are also discussed.
ABSTRACT
The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II's scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers' features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II.
Subject(s)
Adamantane/chemistry , Analgesics/chemistry , Antineoplastic Agents/chemistry , Delayed-Action Preparations/chemistry , Drug Carriers/chemistry , Hypromellose Derivatives/chemistry , Adamantane/pharmacokinetics , Analgesics/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Biomechanical Phenomena , Drug Compounding , Drug Liberation , Humans , In Vitro Techniques , Models, Chemical , Molecular Dynamics Simulation , Structure-Activity RelationshipABSTRACT
The synthesis and pharmacological evaluation of C1-substituted adamantane hydrazones, their C2-substituted isomers, and C1-substituted adamantane furanoic carboxamides is described. These new adamantane derivatives exhibited an interesting pharmacological profile in terms of trypanocidal activity and selectivity. The most active adduct with the best selectivity in this study was found to be the phenylacetoxy hydrazone 1 b (2-[4-(tricyclo[3.3.1.13,7 ]dec-1-yl)phenyl]-N'-[(5-nitrofuran-2-yl)methylene]acetohydrazide; EC50 =11±0.9â nm, SITb =770).
Subject(s)
Adamantane/chemistry , Nifurtimox/chemistry , Trypanocidal Agents/chemical synthesis , Animals , Cell Line , Cell Survival/drug effects , Drug Design , Rats , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effectsABSTRACT
Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Neoplasms/diagnosis , Neoplasms/drug therapy , Receptors, sigma/agonists , Receptors, sigma/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Fluorescent Dyes/chemistry , Humans , Ligands , Molecular Probes , Molecular Targeted Therapy , Radiopharmaceuticals/chemistry , RodentiaABSTRACT
The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of two new tuberculocidal adamantane aminoethers (compounds III and IV), congeneric to the adamantane derivative SQ109, which is in final clinical trials, and aminoethers (I) and (II), using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results suggest that both analogues, albeit more lipophilic than SQ109, and aminoethers (I) and (II), have the requisite in vitro release characteristics for oral administration. In conclusion, these formulations merit further assessment by conducting in vivo studies, at a later stage.
Subject(s)
Adamantane/analogs & derivatives , Antitubercular Agents/chemistry , Delayed-Action Preparations/chemistry , Ethers/chemistry , Ethylenediamines/chemistry , Tuberculosis/drug therapy , Adamantane/administration & dosage , Adamantane/chemistry , Administration, Oral , Antitubercular Agents/administration & dosage , Chemistry, Pharmaceutical , Delayed-Action Preparations/administration & dosage , Drug Compounding/methods , Drug Liberation , Ethers/administration & dosage , Ethylenediamines/administration & dosage , Excipients/chemistry , Hydrogen-Ion Concentration , Solubility , TabletsABSTRACT
The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of 2 new tuberculocidal adamantane aminoethers (compounds I and II), congeneric to the adamantane derivative SQ109, which is in final clinical trials, using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results confirm that both analogues, albeit more lipophilic than SQ109, showed satisfactory in vitro release characteristics from solid pharmaceutical formulations. In conclusion, these formulations merit further assessment by conducting in the future bioavailability in vivo studies.
Subject(s)
Adamantane/analogs & derivatives , Antitubercular Agents/chemistry , Delayed-Action Preparations/chemistry , Drug Liberation , Ethers/chemistry , Adamantane/chemistry , Adamantane/pharmacology , Antitubercular Agents/pharmacology , Cells, Cultured , Drug Compounding/methods , Ethers/pharmacology , Excipients , Molecular Structure , Mycobacterium tuberculosis/drug effects , Solubility , TabletsABSTRACT
BACKGROUND: Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines) 1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'- substituded-[4-(1-adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-adamantyl)- phenoxy]alkylamines 4a,b. METHOD: A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating. RESULTS: The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis. CONCLUSION: The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f,g and 2e,f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring.
