Network Analysis Guided Designing of Multi-Targeted Anti-Fungal Agents: Synthesis and Biological Evaluation.

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), particularly among immunocompromised populations. Candida albicans is one of the most common clinical pathogenic microorganisms which have become a serious health threat to population either infected with Covid-19 or on treatment with immunosuppressant's/broad-range antibiotics. Currently, benzothiazole is a well explored scaffold for anti-fungal activity, especially mercapto substituted benzothiazoles. It is reported that exploring the 2nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, lead optimization approach using bioisosteric replacement protocol was followed to improve the anti-fungal activity of an already reported benzothiazole derivative, N-(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide. To rationally identify the putative anti-candida targets of this derivative, network analysis was carried out. Complexes of designed compounds and identified putative targets were further analyzed for the docking interactions and their consequent retention after the completion of exhaustive MD simulations. Top seven designed compounds were synthesized and evaluated for in-vitro anti-fungal property against Candida, which indicated that compounds 1.2c and 1.2f possess improved and comparable anti-fungal activity to N-(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide and Nystatin, respectively.

In silico anti-SARS-CoV-2 activities of five-membered heterocycle-substituted benzimidazoles.

The manuscript deals with cost-effective synthesis, structural characterization and in silico SARS-CoV-2 screening activity of 5-membered heterocycle-substituted benzimidazole derivatives, 1-((1H-pyrrol-2-yl)methyl)-2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole (L1), 2-(furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole (L2), 2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (L3). The benzimidazole compounds were synthesized through a green-synthetic approach by coupling of 5-membered heterocyclic-carboxaldehyde and o-phenylenediamine in water under an aerobic condition. The compounds were characterized by various spectroscopic methods and X-ray structural analysis. The suitable single-crystals of the methyl derivative of L3 were grown as L3' which crystallized in a monoclinic system and the thiophene groups co-existed in a nearly a perpendicular orientation. Further, in silico anti-SARS-CoV-2 proficiency of the synthetic derivatives is evaluated against main protease (Mpro) and non-structural proteins (nsp2 and nsp7) of SARS-CoV-2. Molecular docking and molecular dynamics analysis of the ligands (L1-L3) against Mpro and nsp2 and nsp7 for 50 ns reveal that L3 turns out to be the superlative antiviral candidate against Mpro, nsp2 and nsp7 of SARS-CoV-2 as evident from the binding score and stability of the ligand-docked complexes with considerable binding energy changes.

Drummondin E and Flinderole B are potential inhibitors of RNA-dependent RNA polymerase of SARS-CoV-2: an in silico study.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected 235.6 million people worldwide. In the present study, RNA-dependent RNA polymerase (RdRp) (PDB Id: 6M71) of SARS-CoV-2, an essential enzyme needed for subgenomic replication and amplification of RNA, was selected. Similar to other RdRps, it is a conserved protein and a popular target for antiviral drug therapy. Based on a computational approach, potential RdRp inhibitors were identified. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of selected molecules were determined using computation tools. The potential inhibitors were docked to the RdRp and later confirmed by Molecular Dynamics (MD) using the "Flare" module of Cresset software. Drummondin E and Flinderole B had higher drug similarity scores among the compounds selected in this study. Both these compounds are noncarcinogenic, nonirritant, nontumorigenic, and nonmutagenic. Molecular docking studies showed that both compounds can bind to RdRp. The best ligand interaction patterns were validated by MD using the "Flare" module. MD was performed for the period of 100 ns with the time step of 1 fs. The simulation results suggest that Thr-680, Arg-624, Lys-676, and Val-557 are key interacting partners in the Drummondin E-RdRp complex, while Asp-618, Asp-760, Asp-623, Arg-624, and Asp-761 are the interacting partners in the Flinderole B-RdRp complex. Based on the in silico drug-likeness score; ADMET properties; and molecular simulation result, we surmise that Flinderole B and Drummondin E could impede SARS-CoV-2 genome replication and transcription by targeting the RdRp protein.

Patients' perspective about speech, swallowing and hearing status post-SARS-CoV-2 (COVID-19) recovery: E-survey.

OBJECTIVE: The present study investigates the COVID-19 survivors' perspective on speech, swallowing, and hearing-related issues post-COVID-19. We further investigate the recovery duration for speech, swallowing, and hearing-related symptoms post-COVID. DESIGN: Survey study; E-survey. METHODOLOGY: A total of 78 subjects (35.78 years ± 11.93) participated in the survey. All the participants were diagnosed with the RTPCR method. To understand the recovery duration for the speech, swallowing and hearing issues post-COVID-19, we conducted a three-phase study. RESULTS: In the first phase of the survey, 68 subjects reported symptoms related to speech, swallowing, and hearing issues 15 days of post-COVID recovery. A total of 76.4% of subjects reported only swallowing-related issues, 4.41% only speech-related issues, whereas 1.47% reported the problem in speech and hearing functions. The 2nd phase of the study was conducted after the first phase of the study. Only 22 subjects reported the presence of swallowing, speech and hearing-related issues from the 68 subjects. During the last phase, only 12 subjects reported speech, swallowing, and hearing issues. All subjects recovered from the olfaction and gustation impairment, whereas 50% of subjects reported the presence of xerostomia. CONCLUSION: From the present study, we conclude that the SARC-CoV-2 virus directly affects the respiratory system and affects the aero-digestive system and laryngeal system physiology. Individuals with comorbid conditions admitted in ICU during COVID-19 treatment and prolonged hospital stay were at higher risk of developing speech, swallowing, and hearing-related issues post-COVID-19. The present study indicated that all COVID-19 survivors should be screened for speech, swallowing, and hearing-related issues for early rehabilitation if needed.

Outcome measures following tele-rehabilitation and conventional face to face rehabilitation in paediatric cochlear implant users during COVID-19 pandemic: A pilot study in a tertiary care setup.

BACKGROUND: Following the COVID-19 pandemic, majority of paediatric cochlear implantees (CI) lost follow ups for rehabilitation and tele-therapy was initiated. Present study thus compared the outcome measures of paediatric CI users on tele-therapy versus conventional face to face therapy following COVID-19 pandemic. METHOD: Twenty seven unilateral paediatric cochlear implantees in the age range of 2-11 years were divided into two groups based on the therapy modality, viz, tele- and face-to-face therapy. Based on the hearing age, participants were further divided into three groups, viz, 0-2, 2-4, and greater than four years. A complete the test battery comprising Integrated Scales of Development, Speech Intelligibility Rating scale, and Revised Categorical Auditory Perception were administered. The speech & language test battery was performed prior to initiating the rehabilitation and post 12 months of rehabilitation. RESULTS: Results of the present study revealed that conventional rehabilitation had better outcomes compared to teletherapy. The rate of progress after one year of rehabilitation with respect to hearing-age showed a significant difference for the hearing-age group of 0-2 years across the domains of audition, speech and language. CONCLUSION: The present study indicates that conventional method of the speech-language and auditory rehabilitation is far better compared to the tele rehabilitation services especially for those visiting tertiary care hospitals as most of them belong to lower and middle socioeconomic status. From the results, it can be delineated that with lesser hearing experience, paediatric CI users always need to initially enroll for conventional therapy for better speech-language and auditory outcomes.