Modifications of flexible nonyl chain and nucleobase head group of (+)-erythro-9-(2′s-hydroxy-3′s-nonyl)adenine [(+)-EHNA] as adenosine deaminase inhibitors. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Kandalkar, Sachin R.; Ramaiah, Parimi Atchuta; Joshi, Manoj; Wavhal, Atul; Waman, Yogesh; Raje, Amol A.; Tambe, Ashwini; Ansari, Shariq; De, Siddhartha; Palle, Venkata P.; Mookhtiar, Kasim A.; Deshpande, Anil M.; Barawkar, Dinesh A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 20(2017)
• Page Start: 5799
• Page End: 5819
• Publication Date: 2017-10-15
• Subjects: ADA -- EHNA -- Nonyl chain modification -- Constrained analogues -- Docking -- Pharmacokinetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.09.015
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III ) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a -7h, 10a-c, 12, 13, 14 and17a-c appeared very potent with Ki values in the low nanomolar range. Thio -analogues of (+)-EHNA24a -e wherein 5′C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds7a ( Ki : 1.1 nM)7b ( Ki : 5.2 nM) and26a ( Ki : 5.9 nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.