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Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs
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- Kang, Dongwei (author)
- Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci,Cheeloo Coll Med, Jinan 250012, Shandong, Peoples R China.;Shandong Univ, Suzhou Res Inst, Jinan 250012, Shandong, Peoples R China.
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- Sun, Yanying (author)
- Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci,Cheeloo Coll Med, Jinan 250012, Shandong, Peoples R China.;Shandong Univ, Suzhou Res Inst, Jinan 250012, Shandong, Peoples R China.
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- Natarajan Arul, Murugan (author)
- KTH,Teoretisk kemi och biologi
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- Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci,Cheeloo Coll Med, Jinan 250012, Shandong, Peoples R China;Shandong Univ, Suzhou Res Inst, Jinan 250012, Shandong, Peoples R China. Teoretisk kemi och biologi (creator_code:org_t)
- 2020-07-03
- 2020
- English.
- In: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 6:8, s. 2225-2234
- Journal article (peer-reviewed)
Abstract
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- Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound 1 (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead K-5a2 was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC50) = 3.30 nM) and mutant strain RES056 (EC50 = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, 8a (half maximal inhibitory concentration (IC50) = 0.028 mu M) was remarkably superior to that of K-5a2 (IC30 = 0.300 mu M) and comparable to that of etravirine (ETR; IC50 = 0.011 EM). Notably, 8a exhibited better druggability than that of K-5a2, including significantly reduced CYP enzymatic inhibitory activity (IC50 > 50 mu M), lower human ether-a-go-go related gene (hERG) inhibition (IC50 > 30 mu M), and improved metabolic stability (short half-life, T-1/2 = 77.5 min) in vitro.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- HIV-1
- NNRTIs
- diarylpyrimidines
- NNIBP
- Tolerant Region I
- thiophene[3
- 2-d]pyrimidine
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- ref (subject category)
- art (subject category)
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