Modifications of flexible nonyl chain and nucleobase head group of (+)-erythro-9-(2’s-hydroxy-3’s-nonyl)adenine [(+)-EHNA] as adenosine deaminase inhibitors

Publication date: Available online 14 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sachin R. Kandalkar, Parimi Atchuta Ramaiah, Manoj Joshi, Atul Wavhal, Yogesh Waman, Amol Raje, Ashwini Tambe, Shariq Ansari, Siddhartha De, Venkata P. Palle, Kasim A. Mookhtiar, Anil M. Deshpande, Dinesh A. Barawkar
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 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-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. Compounds 7a (Ki: 1.1 nM) 7b (Ki: 5.2 nM) and 26a (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.

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