1,2,3-Triazolyl-tetrahydropyrimidine conjugates as potential Sterol Carrier Protein-2 Inhibitors: Larvicidal activity against the Malaria Vector Anopheles arabiensis and In Silico Molecular Docking Study

Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure–activity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules’ potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.Fil: Venugopala, Katharigatta N.. Durban University Of Technology; Sudáfrica. King Faisal University; Arabia SauditaFil: Shinu, Pottathil. King Faisal University; Arabia SauditaFil: Tratrat, Christophe. King Faisal University; Arabia SauditaFil: Deb, Pran Kishore. Philadelphia University Jordan; JordaniaFil: Gleiser, Raquel M.. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinar de Biología Vegetal (P). Grupo Vinculado Centro de Relevamiento y Evaluación de Recursos Agrícolas y Naturales; ArgentinaFil: Chandrashekharappa, Sandeep. National Institute Of Pharmaceutical Education And Research, Raebareli; IndiaFil: Chopra, Deepak. Indian Institute Of Science Education And Research Bhopal; IndiaFil: Attimarad, Mahesh. King Faisal University; Arabia SauditaFil: Nair, Anroop B.. King Faisal University; Arabia SauditaFil: Sreeharsha, Nagaraja. Vidya Siri College Of Pharmacy; India. King Faisal University; Arabia SauditaFil: Mahomoodally, Fawzi M.. University Of Mauritius; MauricioFil: Haroun, Michelyne. King Faisal University; Arabia SauditaFil: Kandeel, Mahmoud. Faculty Of Veteinary Medicine; Egipto. King Faisal University; Arabia SauditaFil: Asdaq, Syed Mohammed Basheeruddin. Almaarefa University; Arabia SauditaFil: Mohanlall, Viresh. Durban University Of Technology; SudáfricaFil: Al-Shari, Nizar A.. Jordan University Of Science And Technology; JordaniaFil: Morsy, Mohamed A.. King Faisal University; Arabia Saudita. Faculty Of Medicine; Egipt

Anti-Tubercular Activity of Substituted 7-Methyl and 7-Formylindolizines and In Silico Study for Prospective Molecular Target Identification

Novel series of diversely substituted indolizines were designed, synthesized, and evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). Many compounds exhibited significant inhibitory activity against MTB H37Rv strains. Indolizines 2d, 2e, and 4 were also found to be active against MTB clinical isolates with multi-resistance to rifampicin and isoniazid. Indolizine 4 was identified as the most promising anti-mycobacterial agent, displaying minimum inhibitory concentration (MIC) values of 4 and 32 μg/mL against H37Rv and MDR strains, respectively. Furthermore, an in silico study was carried out for prospective molecular target identification and revealed favorable interactions with the target enzymes CYP 121, malate synthase, and DNA GyrB ATPase. None of the potent molecules presented toxicity against peripheral blood mononuclear (PBM) cell lines, demonstrating their potentiality to be used for drug-sensitive and drug-resistant tuberculosis therapy

Targeting the DNA Damage Response Machinery for Lung Cancer Treatment

Lung cancer is considered the most commonly diagnosed cancer and one of the leading causes of death globally. Despite the responses from small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients to conventional chemo- and radiotherapies, the current outcomes are not satisfactory. Recently, novel advances in DNA sequencing technologies have started to take off which have provided promising tools for studying different tumors for systematic mutation discovery. To date, a limited number of DDR inhibition trials have been conducted for the treatment of SCLC and NSCLC patients. However, strategies to test different DDR inhibitor combinations or to target multiple pathways are yet to be explored. With the various biomarkers that have either been recently discovered or are the subject of ongoing investigations, it is hoped that future trials would be designed to allow for studying targeted treatments in a biomarker-enriched population, which is defensible for the improvement of prognosis for SCLC and NSCLC patients. This review article sheds light on the different DNA repair pathways and some of the inhibitors targeting the proteins involved in the DNA damage response (DDR) machinery, such as ataxia telangiectasia and Rad3-related protein (ATR), DNA-dependent protein kinase (DNA-PK), and poly-ADP-ribose polymerase (PARP). In addition, the current status of DDR inhibitors in clinical settings and future perspectives are discussed

Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection.

Neisseria meningitidis is the primary cause of bacterial meningitis in many parts of the world, with considerable mortality rates among neonates and adults. In Saudi Arabia, serious outbreaks of N. meningitidis affecting several hundreds of pilgrims attending Hajj in Makkah were recorded in the 2000-2001 season. Evidence shows increased rates of bacterial resistance to penicillin and other antimicrobial agents that are used in the treatment of the meningococcal disease. The host's immune system becomes unable to recognize the polysialic acid capsule of the resistant N. meningitidis that mimics the mammalian cell surface. The biosynthetic pathways of sialic acid (i.e., N-acetylneuraminic acid [NANA]) in bacteria, however, are somewhat different from those in mammals. The largest obstacle facing previously identified inhibitors of NANA synthase (NANAS) in N. meningitidis is that these inhibitors feature undesired chemical and pharmacological characteristics. To better comprehend the binding mechanism underlying these inhibitors at the catalytic site of NANAS, we performed molecular modeling studies to uncover essential structural aspects for the ultimate recognition at the catalytic site required for optimal inhibitory activity. Applying two virtual screening candidate molecules and one designed molecule showed promising structural scaffolds. Here, we report ethyl 3-benzoyl-2,7-dimethyl indolizine-1-carboxylate (INLZ) as a novel molecule with high energetic fitness scores at the catalytic site of the NmeNANAS enzyme. INLZ represents a promising scaffold for NmeNANAS enzyme inhibitors, with new prospects for further structural development and activity optimization

Crystal structure analysis of [5-(4-methoxyphenyl)-2-methyl-2H-1,2,3-triazol-4-yl](thiophen-2-yl)methanone

The title compound, C15H13N3O2S, crystallizes in the monoclinic space group P21/n and its molecular conformation is stabilized via intramolecular C—H...O and C—H...N contacts. The supramolecular structure is mainly governed by C—H...N hydrogen-bonded centrosymmetric dimers, C—H...O and C—H...S hydrogen bonds and S...π and π–π stacking interactions which, together, lead to the formation of a layered crystal packing. The intermolecular interactions were further evaluated through the molecular electrostatic potential map and Hirshfeld fingerprint analysis

Papain-cetylpyridinium chloride and pepsin-cetylpyridinium chloride; two novel, highly sensitive, concentration, digestion and decontamination techniques for culturing mycobacteria from clinically suspected pulmonary tuberculosis cases.

Mycobacterial culture remains the gold standard for the diagnosis of tuberculosis. However, an appropriate digestion and decontamination method (DDM) is essential for the effective recovery of tubercle bacilli in culture. Therefore, the current study was designed to compare the performance of papain-cetylpyridinium chloride [papain-CPC] and pepsin-cetylpyridinium chloride [pepsin-CPC] DDMs against N-acetyl L-Cysteine-sodium hydroxide (NALC-NaOH) DDM for recovery of mycobacteria from clinically suspected pulmonary tuberculosis cases. To evaluate papain-CPC, pepsin-CPC and NALC-NaOH DDMs, sputum samples (N = 1381) were cultured on Löwenstein-Jensen medium and the results were compared. The papain-CPC DDM showed sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 93.27%, 71.7%, and 100%, respectively as compared to NALC-NaOH DDM. Similarly, pepsin-CPC DDM demonstrated sensitivity, specificity, positive predictive value and negative predictive value of 98.94%, 94.7%, 76.11%, and 99.81%, respectively. In summary, both papain-CPC and pepsin-CPC DDMs are highly sensitive and specific techniques for recovery of mycobacteria as compared to NALC-NaOH DDM. However, when the overall performances of all DDMs compared, papain-CPC DDM isolated increased number of mycobacterial isolates with comparatively higher numbers of colonies on LJ media than both pepsin-CPC and NALC-NaOH DDMs, indicating its potential to replace the NALC-NaOH DDM for recovery of mycobacteria from sputum samples

Greener synthesis of indolizine analogues using water as a base and solvent: Study for larvicidal activity against Anopheles arabiensis

Greener synthesis of a series of novel indolizine analogues have been achieved by the cyclization of aromatic cycloimmonium ylides with electron-deficient alkynes in the presence of water as the base and solvent at 80 °C. Yield of the title compounds was good and reactions performed were eco-friendly. The structures of these newly synthesized compounds have been confirmed by spectroscopic techniques such as FTIR, NMR, LC-MS, and elemental analysis. Characterized title compounds were evaluated for larvicidal activity against Anopheles arabiensis by standard WHO larvicidal assay using Temefos as standard at 4 μg/mL. Title compounds 2e, 2f, and 2g emerged as promising larvicidal agents.Fil: Sandeep, Chandrashekharappa. Institute For Stem Cell Biology And Regenerative Medic; IndiaFil: Venugopala, Katharigatta N.. Durban University Of Technology; SudáfricaFil: Gleiser, Raquel M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinar de Biología Vegetal (P). Grupo Vinculado Centro de Relevamiento y Evaluación de Recursos Agrícolas y Naturales; ArgentinaFil: Chetram, Abeen. Durban University Of Technology; SudáfricaFil: Padmashali, Basavaraj. Rani Channamma University; IndiaFil: Kulkarni, Rashmi S.. Jain University; IndiaFil: Venugopala, Rashmi. University Of Kwazulu-natal; SudáfricaFil: Odhav, Bharti. Durban University Of Technology; Sudáfric

Antimycobacterial activity of aqueous and methanol extracts of nine plants against Mycobacterium bacteria

Purpose: The present study was done to evaluate the antimycobacterial activity of aqueous and methanol extracts of nine plants viz., Buddleja saligna, Carpobrotus dimidiatus, Capparis tomentosa, Dichrostachys cinerea, Ekebergia capensis, Ficus sur, Gunnera perpensa, Leonotis leonurus and Tetradenia riparia in South Africa. Methods: Aqueous and methanol extracts of the leaves the plants were tested in vitro for their activity against Mycobacterium smegmatis, Mycobacterium tuberculosis H37Rv (ATCC 25177) and three well-characterized clinical isolates of MDR and XDR-TB isolates using the agar incorporation method. The minimum inhibitory concentration (MIC) of each of the active plant extract was determined using the broth microdilution method. Cytotoxic effect was evaluated against the mouse BALB/C monocyte macrophage (J774.2) and peripheral blood mononuclear cells (PBMCs) whole the toxicity screening was done using the brine shrimp lethality assay. Composition of each of the plants was determined using thin layer chromatography while qualitative analysis of antimycobacterial compounds was done using TLC-Bioautography Results: The methanol extracts of B. saligna, C. tormentosa and C. dimidiatus; and aqueous extracts of G. perpensa and T. riparia possessed significant activity against M. smegmatis, M. tuberculosis H37Rv (ATCC 25177) and the three well-characterized clinical isolates of MDR and XDR-TB. Except for a high concentration of G. perpensa none of the other plants which possessed antimycobacterial activity showed any toxic or cytotoxic activity. Conclusion: Our findings show that B. saligna, C. tormentosa, C. dimidiatus, G. perpensa, and T. riparia have antimycobacterial activity. Further studies would aim at isolation and identification of the active compounds from the plants extracts which had positive antimycobacterial activity