A Retrospective Study to Evaluate Real-world Evidence of Azelnidipine in Indian Patients (REDEFINE Study).

INTRODUCTION: Azelnidipine, a selective calcium channel blocker, effectively lowers blood pressure (BP) and heart rate (HR) in hypertensive patients, as demonstrated in a retrospective real-world evidence (RWE) study in Indian patients. MATERIALS AND METHODS: This was a retrospective cohort study that included 882 patients aged 18 years or older who had been on azelnidipine treatment for the last 3 months for mild to moderate hypertension (HTN). A structured proforma was utilized to gather data from prescribing physicians to assess the efficacy of azelnidipine (8 and 16 mg) as monotherapy or in combination with other antihypertensive drugs. The primary endpoints of the study were to capture changes in systolic blood pressure (SBP) and diastolic BP (DBP) from baseline to the subsequent visits (4 and 12 weeks), while the secondary endpoints were to measure similar changes in the diabetic group and to estimate the proportion of patients achieving target BP of <130/80 mm Hg and <140/90 mm Hg, respectively. RESULTS: The overall mean reduction of systolic/diastolic BP from baseline to 12 weeks was 13.92/7.91 mm Hg (p-value < 0.0001). The mean reduction of systolic/diastolic BP from baseline to 12 weeks was 11.77/7.43 mm Hg (p-value < 0.0001) in newly diagnosed HTN patients, while in known cases of HTN, it was 16.50/8.48 mm Hg (p-value < 0.0001). In the diabetic group, the mean reduction was 15.35/8.69 mm Hg (p-value < 0.0001). Overall the study showed that in 44 (4.99%) and 408 (46.26%) patients, target BP of <130/80 mm Hg and <140/90 mm Hg, respectively was achieved. The mean change in HR from baseline was a reduction of 5.22 beats/minute. CONCLUSION: Azelnidipine can be an effective antihypertensive drug to treat mild to moderate HTN in Indian patients.

Synthesis and pharmacological evaluation of 1,3-diaryl substituted pyrazole based (thio)urea derivatives as potent antimicrobial agents against multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis.

The urgent development of newer alternatives has been deemed a panacea for tackling emerging antimicrobial resistance effectively. Herein, we report the design, synthesis, and biological evaluation of 1,3-diaryl substituted pyrazole-based urea and thiourea derivatives as antimicrobial agents. Preliminary screening results revealed that compound 7a (3,4-dichlorophenyl derivative) exhibited potent activity against S. aureus (MIC = 0.25 µg mL-1) and compound 7j (2,4-difluorophenyl derivative) against Mycobacterium tuberculosis (MIC = 1 µg mL-1). Compounds 7a and 7j were non-toxic to Vero cells with a favorable selectivity index of 40 and 200, respectively, and demonstrated good microsomal stability. Compound 7a exhibited equipotent activity (MIC = 0.25 µg mL-1) against various multidrug-resistant strains of S. aureus, which include various strains of MRSA and VRSA, and elicited bacteriostatic properties. In an enzymatic assay, 7a effectively inhibited DNA gyrase supercoiling activity at a concentration of 8 times MIC. Further, molecular modeling studies suggested that compound 7a binds at the active site of DNA gyrase with good affinity.

An Optimized Deep Learning Approach for the Prediction of Social Distance Among Individuals in Public Places During Pandemic.

Social distancing is considered as the most effective prevention techniques for combatting pandemic like Covid-19. It is observed in several places where these norms and conditions have been violated by most of the public though the same has been notified by the local government. Hence, till date, there has been no proper structure for monitoring the loyalty of the social-distancing norms by individuals. This research has proposed an optimized deep learning-based model for predicting social distancing at public places. The proposed research has implemented a customized model using detectron2 and intersection over union (IOU) on the input video objects and predicted the proper social-distancing norms continued by individuals. The extensive trials were conducted with popular state-of-the-art object detection model: regions with convolutional neural networks (RCNN) with detectron2 and fast RCNN, RCNN with TWILIO communication platform, YOLOv3 with TL, fast RCNN with YOLO v4, and fast RCNN with YOLO v2. Among all, the proposed (RCNN with detectron2 and fast RCNN) delivers the efficient performance with precision, mean average precision (mAP), total loss (TL) and training time (TT). The outcomes of the proposed model focused on faster R-CNN for social-distancing norms and detectron2 for identifying the human 'person class' towards estimating and evaluating the violation-threat criteria where the threshold (i.e., 0.75) is calculated. The model attained precision at 98% approximately (97.9%) with 87% recall score where intersection over union (IOU) was at 0.5.

Isoxazole carboxylic acid methyl ester-based urea and thiourea derivatives as promising antitubercular agents.

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.

Synthesis and evaluation of triazole congeners of nitro-benzothiazinones potentially active against drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy.

With growing concerns regarding target residue mutation hovering over established anti-TB pharmacophores, it is imperative to have reserve chemotypes at our disposal to curb unrestrained spread of tuberculosis. In this context, we herein present the synthesis and bio-evaluation of a library of new nitrobenzothiazinone (BTZ) congeners comprising 2-mercapto/amino-benzothiazinone tethered 1,2,3-triazole hybrids as antitubercular agents. In preliminary screening, 10 out of 37 compounds displayed substantial in vitro potency against Mtb H37Rv (MIC 0.5-8 µg mL-1). Structural optimization of the initial hit 5o (MIC 0.5 µg mL-1) led to identification of linker variants 9a, 9b, 9c, and 9d exhibiting potent anti-TB activity (MIC 0.03-0.12 µg mL-1). When tested against Vero cells to determine their selectivity index (SI), these compounds displayed no appreciable cytotoxicity (SI >80). Further studies on activity against drug resistant (DR) Mtb indicated these compounds to be equally potent (MIC 0.03-0.25 µg mL-1). The in silico covalent docking study suggested a similar polar interaction to that of PBTZ169 with an additional and contrasting side chain interaction at the active site of Mtb DprE1 target protein. Further, the time kill kinetic study found compounds 9a and 9d to be demonstrating bactericidal efficacy, completely eliminating bacilli in 7 days at 10× MIC. The most promising compound 9d, considering its potent anti-TB activity (MIC 0.06 µg mL-1 against drug susceptible Mtb and MIC 0.06-0.25 µg mL-1 against DR Mtb) along with a broad therapeutic index (SI >640) demonstrating a comparable concentration dependent bactericidal efficacy to that of RIF, holds a significant edge to be translated into a potent anti-Mtb agent.

Exploration of 2-phenylquinoline-4-carboxamide linked benzene sulfonamide derivatives as isoform selective inhibitors of transmembrane human carbonic anhydrases.

A novel series of 32 sulfonamide containing quinolines (5a-j, 7a-k and 9a-k) were synthesized using tail approach and assayed for their carbonic anhydrase inhibitory potency against four human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX and XII. Most of these newly synthesized compounds exhibited interesting inhibition potency against hCA I, II, IX and XII, in the nanomolar range with some derivatives being more potent than the standard drug acetazolamide (AAZ). The most effective ones on hCA I were 9b (91.8 nM), on hCA II: 5b (7.1 nM), 9c (9.6 nM) and on hCA IX: 5b (6.5 nM), 5g (21.4 nM), 5i (9.1 nM), 9a (22.8 nM), 9b (9.7 nM). Compounds 5h (8.8 nM), 7a (9.6 nM), 9d (6.9 nM), 9e (6.7 nM) were found highly effective against hCA XII. These 4-functionalized benzenesulfonamides (5a-5j, 9a-9k) were found to be more potent than the corresponding 3-functionalized derivatives (7a-k). These compounds may emerge as potential leads for the development of isoform selective hCA IX and XII inhibitors.

Efficient One-pot Synthesis of 3,3-di(indolyl)indolin-2-ones from Isatin and Indole Catalyzed by VOSO4 as Non-Sulfonamide Carbonic Anhydrase Inhibitors.

BACKGROUND: A high yielding green protocol has been developed and delineated for the synthesis of 3,3- di(indolyl)indolin-2-ones, potentially bioactive compounds, involving one pot aqueous medium condensation of isatin with indole in the presence of VOSO4. The synthesized compounds were screened for their carbonic anhydrase inhibitory activity against human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. These non-sulfonamide derivatives selectively inhibited hCA II in the micromolar range. OBJECTIVE: To develop a high yielding green protocol to synthesize 3,3-diindolyl oxindole derivatives using water as solvent media and screening the synthesized molecules for their carbonic anhydrase inhibitory activity. METHODS: The target compound is obtained by taking isatin, indole, VOSO4, and H2O in one-pot at 70oC. RESULTS: The designed molecules were synthesized by using the new method. The molecules were screened for their CA inhibitory activity, which shows selective inhibition toward hCA II.The result showed an excellent yield without any loss or decrease in catalytic activity, proving the catalyst's performance and recyclability. CONCLUSION: An efficient, simple, and green protocol was established that provides a facile and straightforward approach for the preparation of 3,3-diindolyl oxindole derivatives (3a-r) from Isatin and Indole by using 10 mol% VOSO4 in high yields in a short period of time by a one-pot coupling reaction. Furthermore, the catalyst can also be recovered and reused for three consecutive catalytic cycles without any loss of its efficiency, which was confirmed by performing the experiment with 3a. The newly synthesized molecules (3a-r) were screened for their carbonic anhydrase inhibition potency against four isoforms, hCA I, II, IX, and XII and most of the compounds were found potent against hCA II with potency low to submicromolar range.

Recognition of Ocular Artifacts in EEG Signal through a Hybrid Optimized Scheme.

Brain computer interface (BCI) requires an online and real-time processing of EEG signals. Hence, the accuracy of the recording system is improved by nullifying the developed artifacts. The goal of this proposal is to develop a hybrid model for recognizing and minimizing ocular artifacts through an improved deep learning scheme. The discrete wavelet transform (DWT) and Pisarenko harmonic decomposition are used for decomposing the signals. Then, the features are extracted by principal component analysis (PCA) and independent component analysis (ICA) techniques. After collecting the features, an optimized deformable convolutional network (ODCN) is used for the recognition of ocular artifacts from EEG input signals. When artifacts are sensed, the moderation method is executed by applying the empirical mean curve decomposition (EMCD) followed by ODCN for noise optimization in EEG signals. Conclusively, the spotless signal is reconstructed by an application of inverse EMCD. The proposed method has achieved a higher performance than that of conventional methods, which demonstrates a better ocular artifact reduction by the proposed method.

Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis.

In search of novel therapeutic agents active against emerging drug-resistant Mycobacterium tuberculosis and to counter the long treatment protocol of existing drugs, herein we present synthesis and biological evaluation of a new series of 5-phenyl-3-isoxazolecarboxylic acid methyl ester-chalcone hybrids. Among 35 synthesized compounds, 32 analogues displayed potent in-vitro activity against Mycobacterium tuberculosis H37Rv with MIC 0.12-16 µg/mL. Cell viability test against Vero cells indicated 29 compounds to be non-cytotoxic (CC50 > 20 µg/mL & SI > 10). Most potent compounds with MIC 0.12 µg/mL (7 b, 7j, 7 ab) exhibited selectivity index (SI) in excess of 320. Further studies on activity against drug-resistant Mycobacterium tuberculosis revealed 7j as the most potent compound with MIC 0.03-0.5 µg/mL. Time-kill kinetic study suggested compound 7j displaying concentration-dependent bactericidal killing activity with relatively comparable potency to that of current first-line anti-TB drugs. Taken together, 7j presents a novel hit with potential to be translated into a potent antimycobacterial.