Synthesis of some quinoline-pyrazoline-based naphthalenyl thiazole derivatives and their evaluation as potential antimicrobial agents

Purpose: To prepare and evaluate some quinoline-pyrazoline-based naphthalenyl thiazole derivatives as antimicrobial agents.Methods: Some quinoline-pyrazoline-based naphthalenyl thiazoles (5a-5e and 6a-6e) were prepared by reacting 5-(2-chloroquinolin-3-yl)-3-substitutedphenyl-4,5-dihydro-1H-pyrazole-1-carbothiamides (4a- 4e) with 2-bromo-1-(1-naphthyl)ethanone and 2-bromo-1-(2-naphthyl)ethanone, respectively. Fourier transform infra-red (FTIR), 13C-Nuclear magnetic resonance (13C-NMR), 1H-Nuclear magnetic resonance (1H-NMR), elemental analysis, and mass spectrometry were used to elucidate and confirm the chemical structures of the target compounds. Serial plate dilution technique was used to evaluate the antimicrobial activity of the title compounds using ketoconazole and ofloxacin as standards, and their minimum inhibitory concentrations (MIC) were determined.Results: A total of ten compounds, (5a-5e) & (6a-6e) were prepared. Compound 6d (R = 4-F, naphthalen-2-yl derivative) exhibited antimicrobial activities that were higher than those of the standard drug (ofloxacin) against S. aureus (MIC = 25 μg/mL, p < 0.05), S. epidermidis (MIC = 25 μg/mL, p < 0.0001), K. pneumonia (MIC = 25 μg/mL, p < 0.0001), P. vulgaris (MIC = 25 μg/mL, p < 0.0001) and P.citrinum (MIC = 25 μg/mL, p < 0.0001). Compound 5d (R = 4-F, naphthalen-1-yl derivative) displayed higher antifungal activity than ketoconazole against C. albicans (MIC = 25 μg/mL, p <0.0001).Conclusion: The naphthalen-2-yl derivatives (6a-6e) are superior antimicrobial agents as compared to the naphthalen-1-yl derivatives (5a-5e) and the presence of 4-F substituent in 6d and 5d is essential for stronger antimicrobial activity. The compound 6d needs further investigations related to its safety and efficacy.Keywords: Quinoline, Pyrazoline, Thiazole, Antibacterial, Antifungal, Structure-activity relationshi

Virulence traits and novel drug delivery strategies for mucormycosis post-COVID-19: a comprehensive review

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk

Theoretical and experimental study on lipophilicity and wound healing activity of ginger compounds

Objective: To correlate the chromatographic and computational method to calculate lipophilicity of selected ginger compounds and to observe the effects of log P on wound healing. Methods: Mixtures of acetonitrile and water with acetonitrile content between 95% and 50% v/v in 5% increments were kept separately in 10 different chromatographic chambers, saturated with solvent for 2 h. Spots were observed under UV light at λ=254 nm p-anisaldehyde used as a spraying reagent. Theoretical calculation was done using the Alogps 2.1 online program at www.vcclab.org/lab/alogps. For percentage wound contraction, five groups of animal (mice) (25-30 g) of either sex were selected. Wound were created on dorsal surface of animals using toothed forceps, scalpel and pointed scissors. The wound areas were calculated using vernier caliper. After making wound mice were orally administered 35 mg/kg 6-shogoal, 6-gingerol, 8-gingerol and 10-gingerol respectively. Group E as the control group received tap water. Results: The lipophilicity values determined in thin layer chromatography were correlated with the theoretically calculated various log P by linear regression analysis. Significant correlations were found between log P values calculated by software program and the experimental reversed-phase thin-layer chromatography data. Order of wound healing property of ginger compounds is directly dependent on lipophilicity i.e. more lipophilic compound has highest activity. Conclusions: Experimentally determined lipophilicity (RMO) values were correlated with log P determined by software's and found satisfactory. Lipophilicity (RMO) is a useful parameter for the determination and prediction of biological activity of ginger compounds

Target Based Designing of Anthracenone Derivatives as Tubulin Polymerization Inhibiting Agents: 3D QSAR and Docking Approach

Novel anthracenone derivatives were designed through in silico studies including 3D QSAR, pharmacophore mapping, and molecular docking approaches. Tubulin protein was explored for the residues imperative for activity by analyzing the binding pattern of colchicine and selected compounds of anthracenone derivatives in the active domain. The docking methodology applied in the study was first validated by comparative evaluation of the predicted and experimental inhibitory activity. Furthermore, the essential features responsible for the activity were established by carrying out pharmacophore mapping studies. 3D QSAR studies were carried out for a series of 1,5- and 1,8-disubstituted10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-one derivatives for their antiproliferation activity. Based on the pattern recognition studies obtained from QSAR results, ten novel compounds were designed and docked in the active domain of tubulin protein. One of the novel designed compounds “N1” exhibited binding energy −9.69 kcal/mol and predicted Ki 78.32 nM which was found to be better than colchicine

Synthesis, antiphospholipase A2, antiprotease, antibacterial evaluation and molecular docking analysis of certain novel hydrazones

Some novel hydrazone derivatives 6a-o were synthesized from the key intermediate 4-Chloro-N-(2-hydrazinocarbonyl-phenyl)-benzamide 5 and characterized using IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. The inhibitory potential against two secretory phospholipase A2 (sPLA2), three protease enzymes and eleven bacterial strains were evaluated. The results revealed that all compounds showed preferential inhibition towards hGIIA isoform of sPLA2 rather than DrG-IB with compounds 6l and 6e being the most active. The tested compounds exhibited excellent antiprotease activity against proteinase K and protease from Bacillus sp. with compound 6l being the most active against both enzymes. Furthermore, the maximum zones of inhibition against bacterial growth were exhibited by compounds; 6a, 6m, and 6o against P. aeruginosa; 6a, 6b, 6d, 6f, 6l, 6m, 6n, and 6o against Serratia; 6k against S. mutans; and compounds 6a, 6d, 6e, 6m, and 6n against E. feacalis. The docking simulations of hydrazones 6a-o with GIIA sPLA2, proteinase K and hydrazones 6a-e with glutamine-fructose-6-phosphate transaminase were performed to obtain information regarding the mechanism of action

An Improved Synthesis of Key Intermediate to the Formation of Selected Indolin-2-Ones Derivatives Incorporating Ultrasound and Deep Eutectic Solvent (DES) Blend of Techniques, for Some Biological Activities and Molecular Docking Studies

We have developed a new idea to synthesize a key intermediate molecule by utilizing deep eutectic solvent (DES) and ultrasound in a multistep reaction to ensure process cost-effectiveness. To confirm the stability of reagents with DES, electronic energies were calculated at the B3LYP/6-31+G(d,p) level of theory. DES stabilized the reagents mainly due to strong intermolecular hydrogen bonding. Key intermediate (3) and final compounds (4a–n) were synthesized in a higher yield of 95% and 80%–88%, respectively. Further, final compounds (4a–n) were assessed for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation. The compounds 4f, 4g, 4j, 4l, and 4m showed good anti-inflammatory activity, while 4f, 4i, and 4n exhibited very good analgesic activity as compared to the standard drug. The ulcerogenicity of selected compounds was far less than the indomethacin. The ligands had also shown a good docking score (4f = −6.859 kcal/mol and 4n = −7.077 kcal/mol) as compared to control indomethacin (−6.109 kcal/mol) against the target protein COX-2. These derivatives have the potential to block this enzyme and can be used as NSAID. The state-of-art DFT theory was used to validate the lipid peroxidation mechanism of the active compounds which was in good agreement with the variations of BDEs and IP of the tested compounds

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10–15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed