Synthesis and Modeling Studies of Furoxan Coupled Spiro-Isoquinolino Piperidine Derivatives as NO Releasing PDE 5 Inhibitors.

Swami Prabhuling,Ahmed Al-Harrasi,Yasinalli Tamboli,Prafulla B Choudhari,Tapan Kumar Mohanta,Zubaidha K Pudukulathan,Manish S Bhatia

doi:10.3390/biomedicines8050121

Abstract

Nitric oxide (NO) is considered to be one of the most important intracellular messengers that play an active role as neurotransmitter in regulation of various cardiovascular physiological and pathological processes. Nitric oxide (NO) is a major factor in penile erectile function. NO exerts a relaxing action on corpus cavernosum and penile arteries by activating smooth muscle soluble guanylate cyclase and increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). Phophodiesterase (PDE) inhibitors have potential therapeutic applications. NO hybridization has been found to improve and extend the pharmacological properties of the parental compound. The present study describes the synthesis of novel furoxan coupled spiro-isoquinolino-piperidine derivatives and their smooth muscle relaxant activity. The study reveals that, particularly 10d (1.50 ± 0.6) and 10g (1.65 ± 0.7) are moderate PDE 5 inhibitors as compared to Sidenafil (1.43 ± 0.5). The observed effect was explained by molecular modelling studies on phosphodiesterase.

Highlights

50% of men aged over 40 years suffer from male erectile dysfunction
Synthesis of N-benzyl-2-chloro-N-(2-chloroethyl) ethanamine (2): To a stirred suspension of compound bis(2-chloroethyl) amine hydrochloride (10 mmol) and K2 CO3 (25 mmol) in ACN (10 mL), benzyl bromide (10 mmol) was added dropwise and reaction mixture was stirred for 24 h at ambient temperature
The compound 6 (Supplementary File 1) was obtained by the formation of an amide bond with methyl 2-amino acetate via acid chloride 5 obtained using thionyl chloride

Summary

Introduction

50% of men aged over 40 years suffer from male erectile dysfunction. The relaxation of arterial and trabecular smooth muscle is needed to achieve and maintain the penile erection where vascular diseases have impaired the vasodilator responses. This vasodilator response has been associated with the development of erectile dysfunction and impotence. The treatment options have widened since the launch of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate (ViagraTM). The absence of endogenous nitric oxide (NO) could be rectified by the potential use of NO releasing PDE5 inhibitors under NO-deficient conditions [1]. NO is commonly known as one of the important intracellular messengers and a neurotransmitter [2]

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Conclusion