Indolyl Aryl Sulfones Research Articles

Synthesis of Novel Indolyl Aryl Sulfone-clubbed Hydrazone Derivatives as Potential HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Molecular Modeling and QSAR Studies.

Non-Nucleoside Reverse Transcriptases Inhibitors (NNRTIs) are among the most extensively studied enzymes for understanding the biology of Human Immunodeficiency Viruses (HIV) and designing inhibitors for managing HIV infections. Indolyl aryl sulfones (IASs), an underexplored class of potent NNRTIs, require further exploration for the development of newer drugs for HIV. In this context, we synthesized a series of novels by Indolyl Aryl Sulfones with a hydrazone moiety at the carboxylate site of the indole nucleus. A 2D-QSAR model was developed to predict Reverse Transcriptase inhibitory activity against wild-type RT (WT-RT) enzyme. The model was successfully applied to predict the HIV-1 inhibitory activity of known Indolyl Aryl Sulfones. Considering the reliability, robustness, and reproducibility of the 2D-QSAR model, we made an in-silico prediction of the RT inhibition for our synthesized compounds (1-14). Molecular docking and dynamics simulations established our synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, as effective NNRTIs by stabilizing HIV reverse transcriptase's structure. Binding energy calculations revealed compound 28 as the strongest inhibitor (-43.21 ± 0.09 kcal/mol), followed by 23 (-40.94 ± 0.10 kcal/mol) and 24 (-39.18±0.08 kcal/mol), emphasizing their binding affinity towards HIV reverse transcriptase. In summary, the synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, demonstrate significant potential as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) against HIV. These results highlight the promising role of these compounds in developing novel NNRTIs for managing HIV infections.

Exploration of carboxamide hybrid indolyl aryl sulfones as antiretroviral agents by HIV-1 reverse transcriptase inhibition and antioxidant effects: Synthesis, biochemical screening and computational analysis

Indolyl aryl sulfones (IASs) have been under investigation as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) since the discovery of Merck's compound l-737,126. This research work reports the synthesis of a novel series of indolyl aryl sulfonyl carboxamides (11 to 21 and 25 to 28) and their biological evaluation. Among the synthesized compounds, 15 (IC50 = 57.4 ± 10.1 µM) and 26 (IC50 = 34.0 ± 1.9 µM) demonstrated potent inhibitory activity in RNA-dependent DNA polymerization (RDDP) reactions. In addition, radical inhibition activity was performed by reacting the synthesized compounds against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and it was observed that compounds 20 (IC50 = 8.2 ± 0.2 µM) and 21 (IC50 = 9.3 ± 0.5 µM) showed promising antioxidant properties. Additionally, Two-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) and molecular docking studies were employed to provide insight into the molecular mechanism of RDDP inhibition.

An Overview on Indole Aryl Sulfide/Sulfone (IAS) as Anti‐HIV Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

AbstractSulfur‐containing indoles are widely studied against different biological targets. Among several potential drug candidates, seven molecules of this class are in the current market and a few of them are either in pipeline or in different stages of clinical trials. Particularly, arylthioindoles or indolylarylsulfones (IAS) received great attention by medicinal chemists due to their pharmokinetic profiles and wide spectrum of biological activities like antiviral, anticancer, cardiovascular, and antibacterial properties. This review summarizes the developmental process, synthesis and structure activity relationship (SAR) around arylthioindole/indolylaryl sulfone scaffolds for antiviral/anti‐HIV non‐nucleoside reverse transcriptase inhibitor (NNRTIs) activities. It also offers perspective for further development of 3‐indolylarylsulfones as an anti‐viral agent including their potential against novel COVID‐19 infection.

Computational development of aryl sulfone compounds as potential NNRTIs

Human immunodeficiency virus (HIV) attacks the host’s immune system and affects millions of people globally. Due to the high mutation rate of HIV, it is of great importance that novel drugs are found to combat new strains. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors that bind to the HIV reverse transcriptase and prevent replication. Indolyl aryl sulfones (IAS) and IAS derivatives have been found to be highly effective against mutant strains of HIV-1 reverse transcriptase. Here, we analyzed molecules designed using aryl sulfone scaffolds paired to cyclic compounds (that have previously been found to be beneficial groups for NNRTIs) as potential NNRTIs through the computational design and docking of 100 novel NNRTI candidates. Moreover, we explored the specific combinations of functional groups and aryl sulfones that resulted in the NNRTI candidates with the strongest binding affinity while testing all compounds for carcinogenicity. We hypothesized that the combination of an IAS scaffold and pyrimidine would produce the compounds with the best binding affinity. Our hypothesis was correct as the series of molecules with an IAS scaffold and pyrimidine exhibited the best average binding affinity. Additionally, this study found 32 molecules designed in this procedure with higher or equal binding affinities to the previously successful IAS derivative 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide when docked to HIV-1 reverse transcriptase. These findings contribute to the search for novel NNRTIs as well as expanding knowledge regarding the characteristics of the NNRTI pharmacophore.

Indolylarylsulfones bearing phenylboronic acid and phenylboronate ester functionalities as potent HIV‑1 non-nucleoside reverse transcriptase inhibitors

To explore the chemical space around the entrance channel of the HIV-1 reverse transcriptase (RT) binding pocket, we innovatively designed and synthesized a series of novel indolylarylsulfones (IASs) bearing phenylboronic acid and phenylboronate ester functionalities at the indole-2-carboxamide as new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) through structure-based drug design. All the newly synthesized compounds exhibited excellent to moderate potency against wild-type (WT) HIV-1 with EC50 values ranging from 6.7 to 42.6 nM. Among all, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide and (4-ethylphenyl) boronate ester substituted indole-2-carboxamide were found to be the most potent inhibitors (EC50 = 8.5 nM, SI = 3310; EC50 = 6.7 nM, SI = 3549, respectively). Notably, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide maintained excellent activities against the single HIV-1 mutants L100I (EC50 = 7.3 nM), K103N (EC50 = 9.2 nM), as well as the double mutant V106A/F227L (EC50 = 21.1 nM). Preliminary SARs and molecular modelling studies are also discussed in detail.

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains.

We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7nM; Y181C EC50 = <0.7nM; Y188L EC50 = 21.3nM; K103N-Y181C EC50 = 6.2nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N-Y181C RTs to binary and ternary complexes, respectively.

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043 μM to 4.42 μM. Notably, compound 27 (EC50 = 4.7 nM, SI = 5183) and 33 (EC50 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50 = 0.094 μM), and also showed exceptional activity against E138K (EC50 = 0.014 μM), L100I (EC50 = 0.011 μM) and K103 N (EC50 = 0.025 μM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50 > 234.91 μM, SI > 18727) and 37 (CC50 > 252.49 μM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

Electrooxidative Metal‐Free Dehydrogenative α‐Sulfonylation of 1H‐Indole with Sodium Sulfinates

A method for the electrochemical α‐sulfonylation of 1H‐indole with arenesulfinates was developed. A variety of indoles underwent this sulfonylation smoothly at room temperature under metal‐free and chemical‐oxidant‐free conditions to afford indolyl aryl sulfones in good to high yields. This reaction was found to tolerate a variety of functional groups, including halides and cyclopropyl, ether, ester, and aldehyde groups. It was applied to the synthesis of biologically active 5‐HT6 modulators.

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement

To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.62 μM to 0.006 μM 8 (EC50 = 6 nM) and 18 (EC50 = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC50 = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC50 = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.

In-silico design and study of novel piperazinyl β-carbolines as inhibitor of HIV-1 reverse transcriptase

Despite of all the extensive research work done on recently developed diaryl pyrimidine analogues, thiazolidinedione analogues and indolyl aryl sulfones as HIV-1 reverse transcriptase (RT) inhibitors, there still continues the never-ending problem of resistance. In the present study, we have designed novel β-carboline analogues as inhibitor of HIV-1 RT. Molecular docking studies were performed using Autodock v4.2 against both wild and mutant strains of HIV-1 RT. Among the designed analogues, compound 9H3NH4CN, 9H6CNP and 9H4CN showed significant binding free energy against wild strain (−10.99, −12.06, −11.33 kcal/mol) and against mutant strain (−15.27, −13.9, −15.81 kcal/mol) of HIV-1 RT, respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (−12.02, −8.55 kcal/mol) and against mutant strain (−10.81, −12.1 kcal/mol) of HIV-1 RT, respectively. The predicted inhibitory constant values (K i) of these compounds are against wild strain (8.8, 1.37, 4.92 nM) and against mutant strain (6.4, 64.43, 2.56 pM), respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (1.6, 538.7 nM) and against mutant strain (11.8, 1.36 nM) of HIV-1 RT, respectively. In addition to this, molecular descriptors such as Lipinski drug likeness and ADMET properties were calculated using online servers like Molinspiration and admetSAR. These compounds can be further developed as next generation non-nucleoside reverse transcriptase inhibitors with promising anti HIV-1 activity with better pharmacokinetic profile.

Molecular docking and quantitative structure–activity relationship (QSAR) analyses of indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors

Indolylarylsulfones (IASs) have received considerable interest during the last decades due to high potency against HIV-1 as non-nucleoside reverse transcriptase inhibitors. In present work, quantitative structure–activity relationship (QSAR) and molecular docking analyses were performed to model the anti-HIV-1 activity of 36 IASs. 2D and 3D-descriptors, genetic algorithm, internal and external validations were used to develop statistically robust four-parametric QSAR models. The best QSAR model is with R tr 2 = 0.8608. The QSAR analysis reveals that the activity of IASs depends on the presence of electronegative and heavy atoms at the internal atmosphere of the compounds. The docking analysis reveals that lipophilic and H-bonding interactions are the prominent interactions among IASs and the receptor. The QSAR analysis proved to be a useful tool in the prediction of anti-HIV-1 activity of congeneric compounds and some important insights were also found that will be useful to guide for the synthesis of new IASs with improved activity.

Development of linear and nonlinear predictive QSAR models and their external validation using molecular similarity principle for anti-HIV indolyl aryl sulfones

Quantitative structure–activity relationship (QSAR) studies have been carried out on indolyl aryl sulfones, a class of novel HIV-1 non-nucleoside reverse transcriptase inhibitors, using physicochemical, topological and structural parameters along with appropriate indicator variables. The statistical tools used were linear methods (e.g., stepwise regression analysis, partial least squares (PLS), factor analysis followed by multiple regression (FA-MLR), genetic function approximation combined with multiple linear regression (GFA-MLR) and GFA followed by PLS or G/PLS and nonlinear method (artificial neural network or ANN). In case of physicochemical parameters, GFA-MLR generated the best Equation (n = 97, R2 = 0.862, Q2 = 0.821). Using topological parameters, the best Equation (based on leave-one-out Q2) was obtained with stepwise regression technique (n = 97, R2 = 0.867, Q2 = 0.811). When topological and physicochemical parameters were used in combination, statistical quality increased to a great extent (n = 97, R2 = 0.891, Q2 = 0.849 from stepwise regression). Furthermore, the whole dataset had been divided into test (25% of whole dataset) and training (remaining 75%) sets. Models were developed based on the training set and predictive potential of such models was checked from the test set. The selection of the training set was based on K-means clustering of the standardized descriptors (topological and physicochemical). In this case also the best results were obtained with stepwise regression (n = 72, R2 = 0.906, Q2 = 0.853) but external predictive capacity of this model () was inferior to the model developed from GFA-MLR technique (R2 = 0.883, Q2 = 0.823, ). However, the squared regression coefficient between observed activity and predicted activity values of the test set compounds for the best linear model, i.e., GFA-MLR (r2 = 0.736) was lower in comparison to the best nonlinear model developed using artificial neural network (r2 = 0.781). Thus, based on external validation, the ANN models were superior to the linear models. The predictive potential of the best linear Equation (stepwise regression model) was superior to that of the previously published CoMFA (Q2 = 0.81, SDEPTest = 0.89) on the same data set (Ragno R. et al., J Med Chem 2006, 49, 3172–3184). Furthermore, the physicochemical parameter based models also supported the previous observations based on docking (Ragno R. et al., J Med Chem 2005, 48, 213–223).

Indolyl Aryl Sulfones as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Role of Two Halogen Atoms at the Indole Ring in Developing New Analogues with Improved Antiviral Activity

Indolyl aryl sulfones bearing the 4,5-difluoro (10) or 5-chloro-4-fluoro (16) substitution pattern at the indole ring were potent inhibitors of HIV-1 WT and the NNRTI-resistant strains Y181C and K103N-Y181C. These compounds were highly effective against the 112 and the AB1 strains in lymphocytes and inhibited at nanomolar concentration the multiplication of the IIIBBa-L strain in macrophages. Compound 16 was exceptionally potent against RT WT and RTs carrying the K103N, Y181I, and L100I mutations.

Design, Molecular Modeling, Synthesis, and Anti-HIV-1 Activity of New Indolyl Aryl Sulfones. Novel Derivatives of the Indole-2-carboxamide

Molecular modeling studies and an updated highly predictive 3-D QSAR model led to the discovery of exceptionally potent indolyl aryl sulfones (IASs) characterized by the presence of either a pyrrolidyn-2-one nucleus at the indole-2-carboxamide or some substituents at the indole-2-carbohydrazide. Compounds 7 and 9 were found active in the sub-nanomolar range of concentration in both MT-4 and C8166 cell-based anti-HIV assays. These compounds, and in particular compound 9, also showed excellent inhibitory activity against both HIV-112 and HIV-AB1 primary isolates in lymphocytes and against HIV WT in macrophages.

Indolyl Aryl Sulfones (IASs): Development of Highly Potent NNRTIs Active Against wt-HIV-1 and Clinically Relevant Drug Resistant Mutants

Indolyl aryl sulfones (IASs) are a potent class of NNRTIs developed from L-737,126, a lead agent discovered by Merck AG. IAS derivatives are endowed with inhibitory activities against wt HIV-1 in the low nanomolar concentration range. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of the aryl sulfonyl moiety furnished IAS derivatives such as 5-chloro- or 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide, which showed very potent and selective anti-HIV-1 activity against some mutants carrying NNRTI resistant mutations at positions 103 and 181 of the reverse transcriptase. IAS derivatives bearing 2-hydroxyethylcarboxyamide or 2-hydroxyethylcarboxyhydrazide groups at position 2 of the indole nucleus were more active than L-737,126 against the K103N-Y181C double mutant. A great improvement of antiviral activity against wt HIV-1 and resistant mutants was obtained by coupling 1-3 simple amino acids, such as glycine and alanine, in sequence, with the 3-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-carbonyl moiety. The transformation of the chain terminus into amide or hydrazide, produced short peptides with high selectivity and potent activity against wt HIV-1, and the viral mutants Y181C, K103N-Y181C and EFV(R). IAS having two halogen atoms at the indole showed potent inhibitory activity against the Y181C and the EFV(R) resistant mutant strains. In particular, the introduction of a fluorine atom at position 4 of the indole ring notably contributed to improve the antiviral activities against both wt and the related resistant mutants. 5-Nitro-IASs were highly active against wt HIV-1 and exhibited low cytotoxicity. Experimental data highlighted the class IAS derivatives as promising candidates for clinical trials.

Docking and 3-D QSAR Studies on Indolyl Aryl Sulfones. Binding Mode Exploration at the HIV-1 Reverse Transcriptase Non-Nucleoside Binding Site and Design of Highly Active N-(2-Hydroxyethyl)carboxamide and N-(2-Hydroxyethyl)carbohydrazide Derivatives

Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.

Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: synthesis and SAR studies.

The potent anti-HIV-1 activities of L-737,126 (2) and PAS sulfones prompted us to design and test against HIV-1 in acutely infected MT-4 cells a number of novel 1- and 3-benzenesulfonylindoles. Indoles belonging to the 1-benzenesulfonyl series were found poorly or totally inactive. On the contrary, some of the 3-benzenesulfonyl derivatives turned out to be as potent as 2, being endowed with potencies in the low nanomolar concentration range. In particular, (2-methylphenyl)sulfonyl (72) and (3-methylphenyl)sulfonyl (73) derivatives showed EC(50) values of 1 nM. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of 2 furnished derivatives (80 and 83) which showed very potent and selective anti-HIV-1 activity not only against the wt strain, but also against mutants carrying NNRTI-resistant mutations at positions 103 and 181 of the reverse transcriptase gene.