Synthesis, Molecular Modeling, and Biological Evaluation of Novel Tetrahydro-β-Carboline Hydantoin and Tetrahydro-β-Carboline Thiohydantoin Derivatives as Phosphodiesterase 5 Inhibitors

Two series of fused tetrahydro-β-carboline hydantoin and tetrahydro-β-carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in the β-carboline hydantoin derivatives was found to be essential for the PDE5 inhibition. Chiral carbon derived from amino acid even if of the S configuration (L-tryptophan) may lead to equiactive or more active isomers than those derived from amino acid with the R configuration (D-tryptophan). This expands the horizon from which efficient PDE5 inhibitors can be derived and may offer an economic advantage. The thiohydantoin derivatives were less active than their hydantoin congeners. 1. Introduction Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes responsible for the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) that are important intracellular second messengers playing a central role in regulating many relevant cell functions. These second messengers are converted to the biologically inactive monophosphates with subsequent termination of their physiological functions. Currently, the PDE system includes 11 families (PDE1-PDE11) comprising 21 different gene products [1–3]. The cGMP-specific phosphodiesterase 5 (PDE5) is abundant in the penile tissue, platelets, vascular, and smooth muscle tissues. This enzyme is the primary target for the development of small molecules, such as the well-known sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) to treat erectile dysfunction [4]. Nitric oxide activates guanylatecyclase to convert GTP to the second messenger cGMP which, in turn, results in smooth muscle relaxation and the erectile response. cGMP is hydrolysed by PDE5 to inactive GMP. PDE5 inhibitors such as sildenafil thus act to inhibit cGMP breakdown and thereby facilitate penile erection in patients suffering from MED [5]. Recently, sildenafil was approved for the treatment of pulmonary hypertension (Revatio), and there are numerous emerging reports relating the elevation of cGMP to anticancer apoptotic actions. This further illustrates the potential of PDE5 inhibitors as therapeutic agents. Chemically speaking, the long-acting PDE5 inhibitor tadalafil is considered as a fused tetrahydro-β-carboline piperazinedione derivative with pendant 1,3-benzodioxol moiety at