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Monu Deswal,1 Durgavati Yadav,1 Vinay Kumar,2 Meenakshi Meenu,3 Pranay Tanwar,4 Shivani Srivastava,5 Prabhjot Singh,1 Kumar Sandeep6 1Department of Urology, All India Institute of Medical Sciences, New Delhi, India; 2Heart and Vascular Institute, Pennsylvania State University, Hershey Medical Center, Hershey, PA, USA; 3Department of Pharmacology, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India; 4Lab Oncology Unit, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India; 5Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; 6Preventive Oncology, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence: Prabhjot Singh, Department of Urology, All India Institute of Medical Sciences, New Delhi, India, Email drprabhjotsingh@aiims.edu Kumar Sandeep, Preventive Oncology, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India, Email drkumarsandeep@aiims.eduBackground: Prostate cancer (PCa) is not well understood because of its enormous biological heterogeneity and unreliable progression. We conducted this retrospective analysis to examine the variables predicting early and late progression to castration-resistant PCa (CRPC) for better management of this disease.Methods: This single institutional retrospective study was conducted from January 2018 to January 2022. A total of 98 consecutive men meeting with the diagnosis of CRPC as per the inclusion criteria were included in the study and were stratified in four quartiles on the basis of time to CRPC (time to castration resistance [TTCR]) development. Early CRPC (1st quartile, TTCR = 6– 12 months) and late CRPC (4th quartile, TTCR = 38– 120 months) were then compared on the basis of different clinical, pathological and AR-LBD sequence to find the correlation with response duration.Results: Median time to develop castration resistance was 25 ± 26.44 months. The mean age of the patients was 66.8 ± 9.20 years and median baseline PSA was calculated 100± 685.06 ng/mL respectively. Higher Gleason score (≥ 7– 10) was found to be significantly associated with early development of CRPC (p< 0.001) and lower nadir PSA was significantly indicating late CRPC progression (p< 0.005). No mutations were found in androgen receptor exon-5, 6, 7 except a homozygous mutation in the 7th intronic region, which is involved in splice variants formation playing noteworthy role in CRPC development.Conclusion: Time for metastatic PCa to CRPC ranges from 6– 120 months revealing its heterogeneous nature. Early age presentation in the clinic and high initial PSA and high grade (GS> 7) at diagnosis were positively associated with early CRPC while lower nadir PSA was correlated with late CRPC progression. No remarkable genomic mutations were discovered. Therefore, more data are needed and further research is required with large no. of patients to discover the predictive prognostic biomarkers for better patients’ management.Keywords: prostate cancer, castration resistance, early and late progression, PSA, androgen receptor, PCa

This study focuses on the efficient synthesis of series of substituted 4-amino-6-(1H-benzimidazol-2-ylsulfanyl) benzene-1,3-dicarbonitrile derivatives synthesized from aldehydes, propanedinitrile, substituted thiols and catalyzed by ZnO nanoparticles (ZnONPs). All the synthesized compounds have been characterized using different spectroscopic techniques such as FT-IR, 1H-NMR, C13-NMR and Mass. The compounds were evaluated for potential pharmacological applications, including antimicrobial, α-amylase inhibitory and anticancer activities. Computational calculations, DFT, in-silico molecular docking, and ADME-toxicologystudies were performed. ADMET studies indicated that all synthesized compounds adhered to Rule of five with good bioavailability. This research underscores the promising pharmacological prospects of the synthesized newbenzimidazole derivatives.

Six benzimidazole derivatives have been synthesized and characterized using spectroscopic techniques such as IR, 1H NMR, 13C NMR, and mass spectrometry. The computational calculations and geometrical optimization of newly synthesized benzimidazole derivatives were investigated using Gaussian software in conjunction with the Density functional theory (DFT)/B3LYP method with a 6–311++G(d,p) basis set at gaseous phase. In addition, the quantum chemical parameters of the compounds were evaluated to comprehend the structural activity concept. The synthesized compounds were tested for cytotoxicity using the MTT assay and antioxidant activity using the DPPH scavenging activity and the Ferrous-Ion Chelating Assay. All the compounds tested showed antioxidant, antidibetic, cytotoxic potential, with compounds 4c and 4f being the best of all derivatives. The agar diffusion method was used to conduct antimicrobial assays for bacteria and fungi. Even though none of the compounds were found to be effective against fungi isolates and some had a poor anti-bacterial effect, compound 4f had a significantly higher antibacterial effect against all bacteria strains (S. aureus, Bacillus cereus, E. coli, and Acetobacter sp.). Furthermore, in vitro anticancer properties of synthesized compounds were validated using in silico molecular docking simulation studies. Compound 4c had the highest binding affinity of all the ligands, with a binding energy of −5.9 Kcal/mol and three hydrogen bonds.