A Novel Artificial Intelligence and Machine learning-based scoring system for evaluating re-purposing potential of Valproic Acid drug in COVID-19.

Background Despite widespread vaccinations and the introduction of many repurposed medications, the rise of COVID-19 reinfection due to the SARS-CoV Omicron (B.1.1.529) variant has presented a significant challenge to health authorities across the world. There is a critical need for novel healthcare medications. Valproic acid (VPA) has been reported to be a beneficial drug due to its excellent property to hinder enveloped viral multiplication. Artificial Intelligence (AI) and Machine Learning (ML) have been used extensively to predict the repurposing potential of a drug by examining its past couple of years’ activity. The strategies for drug repositioning that will play a substantial role in this approach can be widely categorized into AI approaches, network-based models, and structure-based approaches. Methodology We have implemented a multimodal pipeline that operates on computational and machine learning strategies, namely molecular docking, molecular data, chemical information, clinical data, and gene expression to analyze the drugs for their sensitivity against covid-19. Here, we implemented the COV-DrugX pipeline to comprehend the physicochemical properties of VPA interactions with viral protein (targets), identify a place in the gene expression profile, additionally its potential role in human network databases. Result and Conclusion Here, we have analyzed the ML pipeline developed by our research group (Rawal et al., 2021) to identify the COVID-associated drug repurposing properties through AI and learning prediction module and use the COV-DrugX pipeline, that predicts the repurposing properties between different existing COVID-19 drugs. Nsp13 was found to have the highest binding affinity (-5.6 kcal/mol) with VPA. By using different modules, we have found that VPA displays physicochemical, biological, and other characteristics similar to existent COVID-19 drugs

Chemoselective Azidation of <i>o</i>‑Alkynylaldehydes over [3 + 2] Cycloaddition and Subsequent Staudinger Reaction: Access to Benzonaphthyridines/Naphthyridines

An efficient tandem approach for the chemoselective synthesis of functionalized azido-pyranoquinolines and azido-iodo-pyranoquinolines via electrophilic cyclization of <i>o</i>-alkynylaldehydes in the presence of sodium azide under mild reaction conditions is described. Mechanistic studies confirm the formation of azido-pyranoquinolines through nucleophilic attack of azide on pyrilium intermediate over [3 + 2] cycloaddition of the azide on the alkyne. The synthesized azido-pyranoquinolines were transformed into benzonaphthyridines via Staudinger reaction. The mechanistic pathway was supported by deuterium labeling experiment and X-ray crystallographic studies

Unveiling the Three-Component Phosphonylation on Alkynylaldehydes: Toolbox toward Fluorescent Molecules

A regioselective tandem approach for annulated napthyridines/isoquinolines embedded with the phosphine oxide group under mild reaction conditions has been achieved in good to excellent yields. The designed strategy involves the triflate-induced formation of new C sp3–P and C sp2–N bond formation in one pot. This protocol was also well tolerated for the construction of densely functionalized organo-phosphorylated chromenes in good yields. Further, phosphino-derived sulfamethazine and sulfamethoxazole drugs were also successfully synthesized in good yields. The mechanistic studies revealed that the ionic pathway and the formation of regioselective 6-endo dig cyclized products were confirmed through X-ray crystallographic studies. Interestingly, photophysical studies of selectivity selected compounds revealed their stimulating fluorescence properties

Palladium-Catalyzed Intramolecular Fujiwara-Hydroarylation: Synthesis of Benzo[<i>a</i>]phenazines Derivatives

An atom-economical Pd-catalyzed approach for the synthesis of benzophenazine derivatives using substituted 2-aryl-3-(aryl/alkylethynyl) quinoxaline in the presence of trifluoroacetic acid at 65 °C has been described. The chemistry involves in situ generation of cationic Pd­(II) species, which functionalized the aromatic C–H bonds via electrophilic metalation followed by concomitant intramolecular trans-insertion of C–C triple bond to aryl-Pd complex. The results were supported by various control experiments including with electron–deficient arenes and deuterium labeling studies. The deuterium labeling studies supports electrophilic palladation of aromatic C–H over activation of C–C triple bond of alkyne. The structure of synthesized compounds was further confirmed by X-ray crystallography studies. This catalytic protocol has been efficiently applied for novel synthesis of highly functionalized benzo fused phenazines

Tandem Synthesis of Pyrroloacridones via [3 + 2] Alkyne Annulation/Ring-Opening with Concomitant Intramolecular Aldol Condensation

An efficient cascade strategy for the direct synthesis of pyrrolo­[3,2,1-<i>de</i>]­acridones <b>4a</b>–<b>v</b>, <b>5a</b>–<b>h</b> from iodo-pyranoquinolines <b>2a</b>–<b>i</b> by the palladium-catalyzed regioselective [3 + 2] alkyne annulation/ring-opening followed by intramolecular aldol condensation under microwave irradiation is described. The chemistry involves the in situ formation of pyrroloquinolines <b>Y</b>, via palladium-catalyzed selective [3 + 2] annulation of iodopyranoquinolines and internal akynes with ring-opening and successive intramolecular cross-aldol condensation. Both the symmetrical and unsymmetrical internal alkynes were reacted smoothly to provide the desired pyrroloacridones in good yields. This methodology provides the facile conversion of easily accessble iodopyranoquinoline into highly functionalized biologically important pyrroloacridones in a single process

Site-Selective Electrophilic Cyclization and Subsequent Ring-Opening: A Synthetic Route to Pyrrolo[1,2‑<i>a</i>]quinolines and Indolizines

An efficient strategy for the synthesis of pyrrolo­[1,2-<i>a</i>]­quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-<i>endo</i>-<i>dig</i> cyclized products. Quantum chemical calculations between C–N (Δ<i>E</i>_a = 9.01 kcal/mol) and C–C (Δ<i>E</i>_a = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic studies. Iodo-substituted compounds generated by the electrophilic iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions

Site-Selective Electrophilic Cyclization and Subsequent Ring-Opening: A Synthetic Route to Pyrrolo[1,2‑<i>a</i>]quinolines and Indolizines

An efficient strategy for the synthesis of pyrrolo­[1,2-<i>a</i>]­quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-<i>endo</i>-<i>dig</i> cyclized products. Quantum chemical calculations between C–N (Δ<i>E</i>_a = 9.01 kcal/mol) and C–C (Δ<i>E</i>_a = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic studies. Iodo-substituted compounds generated by the electrophilic iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions

Site-Selective Electrophilic Cyclization and Subsequent Ring-Opening: A Synthetic Route to Pyrrolo[1,2‑<i>a</i>]quinolines and Indolizines

An efficient strategy for the synthesis of pyrrolo­[1,2-<i>a</i>]­quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-<i>endo</i>-<i>dig</i> cyclized products. Quantum chemical calculations between C–N (Δ<i>E</i>_a = 9.01 kcal/mol) and C–C (Δ<i>E</i>_a = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic studies. Iodo-substituted compounds generated by the electrophilic iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions

Palladium-Catalyzed Regioselective [3 + 2] Annulation of Internal Alkynes and Iodo-pyranoquinolines with Concomitant Ring Opening

A regioselective tandem synthesis of highly functionalized pyrrolo[1,2-<i>a</i>]quinolines has been developed through a novel strategy by palladium-catalyzed [3 + 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with <i>n</i>-alkyl substitution at the 3-position leads to the formation of pyrrolo-acridones <i>via</i> [3 + 2] annulations/ring opening and successive intramolecular cross-aldol condensation