title: Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors.
abstract: Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.50, 98.07, 91.24, 85.27, 77.59, 84.11 & 76.49% inhibition) enzyme activity. Further, cell based assay showed that compounds 4, 5, 8 &12 are identified as the best compounds of the series (EC(50) ranged from 0.09 to 0.8 μg/ml and 0.12 to 1.06 μg/ml) against HIV-1 III(B) and HIV-1 ADA5 strains, respectively. Moreover, the compounds which were active against HIV-1 III(B) and HIV-1 ADA5 were also found to be active against primary isolates (EC(50) ranged from 0.10 to 1.55 μg/ml against HIV-1 UG070 and 0.07 to 1.1 μg/ml against HIV-1 VB59), respectively. Structure-activity relationship (SAR) studies demonstrated the importance of the lipophilic bulky substituent pattern on compact heteroaryl ring at N-3, replacement of C4' at C-2 phenyl by trivalent bioisosteric nitrogen and dihalo groups at C-2 aryl/heteroaryl of thiazolidin-4-ones is crucial for anti-HIV-1 activity. Molecular modeling of compounds 4, 5, 8 and 12 in complex with HIV-1 RT demonstrate that there is good correlation of results obtained from SAR studies. Therefore the compounds 4, 5, 8 and 12 may be considered as good candidates for further optimization of anti-HIV-1 activity.
authors: Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors: Vanangamudi
authors: V
authors: Murugesan
authors: Vinay S
authors: VS
authors: Tiwari
authors: Reshu
authors: R
authors: Saxena
authors: Rajkamal
authors: R
authors: Tripathi
authors: Ramesh
authors: R
authors: Paranjape
authors: Smita
authors: S
authors: Kulkarni
authors: Nandini
authors: N
authors: Makwana
authors: Rahul
authors: R
authors: Suryawanshi
authors: Seturam B
authors: SB
authors: Katti
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase