Diwakar Rai

Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: Design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives

In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies.

Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays

Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.

Synthesis and Anti-HIV Activity of 4-(Naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl Derivatives

A series of 4‐(naphthalen‐1‐yl)‐1,2,5‐thiadiazol‐3‐hydroxyl derivatives (Ia–Im and IIa–IIe) designed as novel HIV‐1 non‐nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized via an expeditious route and evaluated for their anti‐HIV activities in MT‐4 cell cultures. All the synthesized compounds were structurally confirmed by spectral analyses. Biological results showed that three analogues displayed moderate inhibitory activity against wild‐type (wt) HIV‐1 replication with EC50 values ranging from 16 to 22 μm. Molecular docking of compound Ih with wt HIV‐1 RT was performed to understand the binding mode between these inhibitors and the wt HIV‐1 RT and to rationalize some SARs.

Non-nucleoside anti-HBV agents: advances in structural optimization and mechanism of action investigations

Hepatitis B is an infectious inflammatory disease of the liver, which is caused by the hepatitis B virus (HBV). Nowadays, the dramatic development of new HBV inhibitors is focused on discovering diverse non-nucleoside compounds with either novel structures or new mechanisms of action. In this review, we focus on the recent advances in discovery, structural modifications and biological activities studies of several distinct classes of synthetic non-nucleoside small molecular compounds with new mechanisms.

Recent Advances in the Research of 2,3-Diaryl-1,3-thiazolidin-4-one Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Derived from the structure of 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), 2,3-diaryl-1,3-thiazolidin-4-one derivatives became a novel class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Under the guidance of continuous structure-activity relationship (SAR) analysis and molecular modeling, various structural modifications were carried out on nearly all the positions of the thiazolidin-4-one nucleus. Some of the derivatives proved to be highly effective against HIV-1 replication at 10-40 nanomolar concentration ranges with minimal cytotoxicities. In this article, the whole development of 2,3-diaryl-1,3-thiazolidin-4-one series from the discoveries to recent advances, their panoramic SAR studies and binding modes based on molecular modeling were reviewed, and also some enlightenments for further investigation were presented.

Recent advance of the hepatitis B virus inhibitors: a medicinal chemistry overview

Hepatitis B Virus (HBV) is one of the most prevalent viral infections of human worldwide. The therapies are limited in the clinical context because of negative side effects of interferons and the development of viral resistance to the nucleoside/nucleotide inhibitors. In this review, we summarize the recent advances in design and development of potent anti-HBV inhibitors from natural sources and synthetic compounds, targeting different steps in the life cycle of HBV. We attempt to emphasize the major structural modifications, mechanisms of action and computer-aided docking analysis of novel potent inhibitors that need to be addressed in the future to design potent anti-HBV molecules.

Design, synthesis, and biological evaluation of novel 3,5-disubstituted-1,2,6-thiadiazine-1,1-dione derivatives as HIV-1 NNRTIs.

On the basis of structural features, binding mode, and structure–activity relationship studies of two pyrimidine‐derived non‐nucleoside reverse‐transcriptase inhibitors, DABOs, and diaryl pyrimidines, a novel class of 1,2,6‐thiadiazine‐1,1‐dione derivatives were rationally designed using the strategies of bioisosterism and molecular hybridization, synthesized, and evaluated for their anti‐HIV activity in MT4 cell cultures. Three compounds were found to have moderate activity against HIV‐1 replication with EC50 values ranging from 23 to 32 μm. To further confirm the binding target, compound IIg was selected to conduct an HIV‐1 reverse‐transcriptase inhibitory assay. In addition, preliminary structure–activity relationship analysis among the newly synthesized compounds was discussed, and the binding mode of the active compound IIg was rationalized by molecular docking and physicochemical studies.

Design, synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs

A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a-8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC(50)=0.05-35 μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC(50)=0.07 μM, CC(50) >347 μM, SI >4870; EC50=0.05 μM, CC(50)=42 μM, SI=777, respectively), comparable to that of the marked drug nevirapine (EC(50)=0.113 μM, CC(50) >15 μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties.