Design Synthesis and Pharmacological Evaluation of Novel Phosphodiesterase FourInhibitors for their Anti Depressant and Anxiolytic Potential

Abstract

Phosphodiesterase-4(PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to theinactive monophosphate. Their inhibitors may offer novel strategies in the treatment of depression. However, its development as antidepressant drugs has been encumbered by their side effects profile of non-selective PDE inhibitors like nausea, emesis,gastrointestinal side-effects, and vascular toxicity. These side-effects can be minimized by specifically targeting isozymes in the particular tissue or the cell of interest. So, we were interested in developing novel, PDE4 inhibitors with better isozyme selectivity and further explore their potential as anti-depressant and anxiolytics.The novel pharmacophoric requirements derived from nitraquazone and its related compounds as potential PDE4 inhibitors that include key elements: a) a planar scaffold providing a HBA and b) two hydrophobic substituent s with their corresponding linker(1 and 2). On the basis of the proposed pharmacophore, six different series of N4 newlinesubstituted quinoxaline based carboxamides with variations on linker-1 and/or newlineunsubstituted/substituted hydrophobe, and while two series of N3 substituted quinazoline newlinebased carboxamides which are positional isomer of quinoxaline-carboxamides were newlinedesigned as per the pharmacophoric requirements as novel PDE4 inhibitors. newlineThe first series comprises of linker-1 having alkyl group and unsubstituted hydrophobe newlinei.e., benzyl (QCA), while in second series substituted hydrophobe having strong newlineactivating group (OCH3) at para-position i.e., 4-methoxybenzyl (QCB), and in third series newlinesubstituted hydrophobe having strong deactivating group (CN) at para-position i.e., newline4-cyanobenzyl (QCC) were designed and synthesized. Similarly unsubstituted newlinehydrophobe with linker-1 having carbonyl group viz., benzoyl (QCD), or having both alkyl newlineand carbonyl group i.e., 2-phenylacetyl (QCE), or (n = 2) increased alkyl chain length i.e., newlinephenethyl (QCF), while two series of N3 substituted