Compound 3c Research Articles

Synthesis of thiazolidine-2,4-dione tethered 1,2,3-triazoles as α-amylase inhibitors: In vitro approach coupled with QSAR, molecular docking, molecular dynamics and ADMET studies

A new series of thiazolidine-2,4-dione tethered 1,2,3-triazole derivatives were designed, synthesized and screened for their α-amylase inhibitory potential employing in vitro and in silico approaches. The target compounds were synthesized with the help of Cu (I) catalyzed [3 + 2] cycloaddition of terminal alkyne with numerous azides, followed by unambiguously characterizing the structure by employing various spectroscopic approaches. The synthesized derivatives were assessed for their in vitro α-amylase inhibition and it was found that thiazolidine-2,4-dione derivatives 6e, 6j, 6o, 6u and 6x exhibited comparable inhibition with the standard drug acarbose. The compound 6e with a 7-chloroquinolinyl substituent on the triazole ring exhibited significant inhibition potential with IC50 value of 0.040 μmol mL−1 whereas compound 6c (IC50 = 0.099 μmol mL−1) and 6h (IC50 = 0.098 μmol mL−1) were poor inhibitors. QSAR studies revealed the positively correlating descriptors that aid in the design of novel compounds. Molecular docking was performed to investigate the binding interactions with the active site of the biological receptor and the stability of the complex over a period of 100 ns was examined using molecular dynamics studies. The physiochemical properties and drug-likeliness behavior of the potent derivatives were investigated by carrying out the ADMET studies.

Synthesis and In-silico Docking Analysis of 2-Phenylindolizine Acetamide Scaffolds: Potent Anticancer and Antibacterial Ta

Background: Although several specialized methods for treating various cancers have been developed, clinical outcomes for patients with colon cancer have shown unfavorable effects in addition to chemotherapeutic drug resistance. Therefore, finding medicinal substances with minimal to no side effects is crucial in the fight against cancer. Further, this study underscores the significance of 2-phenylindolizine acetamide due to the diverse biological features and the extensive application of this moiety as an effective anticancer and antibacterial drug. Objective: The goal of the study was to investigate novel, prospective 2-phenylindolizines as anticancer and antibacterial drugs. Methods: The synthesized compounds were characterized by different spectral analyses like 1 H NMR, 13C NMR, IR, and mass spectrometry. Pharmacokinetics in-silico studies were performed to predict the drug performance in the body using the SwissADME kit. The molecular docking was performed to check the catalytic binding site between the Topoisomerase-IV from S. pneumoniae and synthesized compounds. The antibacterial activity was assessed using the agar well diffusion method, and the compounds were screened for in vitro anticancer activity using an MTT assay with doxorubicin as a reference. Results: Interestingly, 2-phenylindolizine scaffolds 7c, 7f, and 7g revealed a remarkable antibacterial activity against relevant organisms S. aureus, E. coli, S. pneumoniae, and P. aeruginosa. The target compounds 7e and 7h showed excellent anticancer activity against Colo-205 and MDA-MB-231 cell lines with IC50 values of 68.62, 62.91, 54.23, and 46.34 µM, respectively. Compounds 7a, 7f, and 7c exhibited the highest hydrogen bonding amino acid interactions Asp83 (2.23 Å), Asp83 (2.08 Å), His74 (2.05 Å), His76 (1.71 Å), and Ser80 (1.05 Å) with active site of Topoisomerase-IV from S. pneumoniae (4KPE). Conclusion: This research focused on recent advances in drug design and development, as well as Phenylindolizine derivatives and how they work on anticancer and antibacterial sites of action.

Immunomodulation and anticancer evaluation of quinazoline-based thalidomide analogs: Design, synthesis, docking, and dynamic simulation

A new series of thalidomide analogs were synthesized and evaluated against HepG-2, HCT-116, PC3, and MCF-7. With IC50 values ranging from 2.41 to 14.78 μM, compounds 4c, 5g, and 7 demonstrated substantial potencies against all examined cell lines in comparison to thalidomide (IC50 = 32.12 - 76.91 μM)). The most active compounds were further evaluated for their in vitro immunomodulatory activities via IL6, TNF-α and human caspase-3 in MCF-7 cells using thalidomide as a positive control. Compounds 5g and 4c showed significant reductions in IL6 (80.65 %) and TNF-α (76.14 %), compared to thalidomide (45.11 % and 41.39, respectively). Furthermore, compound 4c exhibited a significant elevation in caspase-3 level (409.33 pg/mL) compared to thalidomide (349.55 pg/mL). In addition, the most active compounds were examined for their COX-I, COX-II, VEGFR inhibitory activities. Compound 5g was the most active member against COX-I (0.80 μM), compound 4c was the most active member against COX-II (0.80 μM), and compound 4c was the most active member against VEGFR (253 nM). Furthermore, the flowcytometry analyses revealed that compound 4c can arrest the cell line at Pre-G1 phase and induce a significant apoptotic effect (75.75 %) compared to control cells (2.62 %) and thalidomide (65.34 %). Our derivatives were subjected to molecular modeling to assess their binding to Cereblon and also dynamic simulations.

Quantum chemical modelling, molecular docking, synthesis and experimental anti-microbial activity of 1,4-diazepan linked piperidine derivative

BackgroundIn this work, we represent synthesis, in silico analysis and biological activity of 1,4 diazepine linked piperidine derivatives (6a–6o). All the derivatives were screened for their anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. Compounds were synthesized from reaction of tert-butyl 1,4-diazepane-1-carboxylic, butyryl chloride and varied aromatic aldehyde, further characterized by 1H NMR and LCMS spectral techniques.ResultUsing ampicillin as a positive control, the synthetic compounds 6a–6o were tested for their in-silico study and experimental anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. According to in vitro assay compound 6a, compound 6c, compound 6d, compound 6m and compound 6I showed higher activity against all the tested strains. Molecule 6i, compound 6j, compound 6k, compound 6f has good to moderate antibacterial activity. DFT computations were used to optimize the molecular geometry at the B3LYP/6-31G (d, p) theoretical level. The corresponding energy values of molecular orbitals were visualized using optimized geometries. Moreover, Auto Dock Vina 1.2.0 is used to assess molecular docking against two target proteins, Bacillus subtilis (PDB ID: 6UF6) and Protease Vulgaris (PDB ID: 5HXW). The target molecule 6b displayed the best binding energies for both. Additionally, we calculated the ADME for each molecule (6a–6o).ConclusionAll fifteen synthesized compounds were screened for their in vitro and in silico analysis. In vitro analysis for anti-microbial activity was carried out against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria and compound 6a, compound 6c, compound 6d, compound 6m and compound 6I exhibits more potent activity towards all tested strains. Molecular docking is performed against target proteins, L-amino acid deaminase from Proteus Vulgaris and LcpA ligase from Bacillus subtilis, representing the Gram-negative bacterium and Gram-positive bacterium, respectively. Compound 6b showed the highest no. of interaction with protein according to molecular docking. With the advent of innovative techniques like ADME, we select their hit compounds early on and anticipate future pharmacokinetic and pharmacodynamic benefits and drawbacks of these promising therapeutic candidates.Graphical abstract

Novel pyrrolidine-alkylamino-substituted dicyanoisophorone derivatives as near-infrared fluorescence probe for imaging β-amyloid in vitro and in vivo

BackgroundThe formation of amyloid-β (Aβ) plaques is one of the key neuropathological hallmarks of Alzheimer's disease (AD). Near-infrared (NIR) probes show great potential for imaging of Aβ plaques in vivo and in vitro. Dicyanoisophorone (DCIP) based Aβ probes have attracted considerable attention due to their exceptional properties. However, DCIP probes still has some drawbacks, such as short emission wavelength (<650 nm) and low fluorescence intensity after binding to Aβ. It is clear that further modification is needed to improve their luminescence efficiency and sensitivity. ResultsWe designed and synthesize four novel pyrrolidine-alkylamino-substituted DCIP derivatives (6a-d) as imaging agents for β-amyloid (Aβ) aggregates. Compound 6c responds better to Aβ aggregates than the other three compounds (6a, 6b and 6d) and its precursor DCIP. The calculated detection limit is to be as low as 0.23 μM. Compound 6c shows no cytotoxicity in the tested concentration for SH-SY5Y and HL-7702 cells. Additionally, compound 6c is successfully applied to monitor Aβ aggregates in live SH-SY5Y cells and APP/PS1 transgenic mice. The retention time in the transgenic mice brain is much longer than that of age-matched wild-type mice. SignificanceThe results indicates that compound 6c had an excellent ability to penetrate the blood-brain barrier and it could effectively distinguish APP/PS1 transgenic mice and wide-type mice. This represents its promising applications for Aβ detection in basic and biomedical research.

Facile synthesis, crystal structure, Hirshfeld surface analysis, DFT calculations, IR and UV–visible spectra analyzes, ADMET and molecular docking studies of arylideneisoxazolone derivatives

Isoxazolone derivatives exhibit numerous biological and pharmacological activities. The search of new procedures for the synthesis of this class of heterocycles is still relevant. Thus we propose a new efficient method for the preparation of a series (4a-4j) of 3-methyl-4-arylidene-isoxazol-5(4H)-ones by the three-component reaction between aromatic aldehydes, ethyl acetoacetate and hydroxylamine hydrochloride, catalyzed by sulfamic acid as an inexpensive, commercially available and easy to handle catalyst. The expected molecules were obtained, in general, in good yields in relatively short reaction times and their structures were elucidated by 1H and 13C NMR and high resolution mass spectrometry for the new compounds. In addition, the structure of compound 4c was confirmed by X-ray diffraction and its Hirshfeld surface analyzed. The work is complemented by theoretical studies including DFT calculations, IR vibrations and UV–Vis electronic transitions analyzes and ADMET properties. In Silico physicochemical properties as well as molecular docking were also carried out.

Discovery of α-hexyl cinnamaldehyde and its derivatives as novel larvicides against Aedes albopictus

Mosquitoes are the vectors of numerous diseases such as malaria, Dengue and Zika. Controlling mosquito vectors is essential for preventing and managing diseases transmitted by mosquitoes. Larvicides target larvae within their breeding habitats before they mature into adult mosquitoes and disperse. In this study, using α-hexyl cinnamaldehyde (HCA) as a lead compound, three series of derivatives comprising a total of 78 compounds were designed and synthesized. The larvicidal activities of these compounds against Aedes albopictus were evaluated, resulting in the identification of ten promising compounds. Among them, furan-3-ylmethyl cinnamate (compound 2v) and (E)-allyl 3-(4-chlorophenyl)acrylate (compound 4c) exhibited the lowest LC50 values (8.0 ppm and 7.2 ppm respectively). In a 96-h acute toxicity assay conducted on zebrafish, 2v showed no or very low toxicity with an LC50 higher than 100 ppm. To elucidate their mode of action, morphological and histopathologic analyses were performed, and the effects of the compounds on the acetylcholinesterase (AChE) and phosphatase activities were evaluated. Results suggested that the active HCA derivatives induce injury to intestinal epithelial cells by inhibiting phosphatase activity, ultimately resulting in the mortality of mosquito larvae.

Design and Synthesis of Polyphenolic Imidazo[4,5-c]quinoline Derivatives to Modulate Toll Like Receptor-7 Agonistic Activity and Adjuvanticity.

TLR-7/8 agonists are a well-known class of vaccine adjuvants, with a leading example now included in Covaxin, a licensed human COVID-19 vaccine. This thereby provides the opportunity to develop newer, more potent adjuvants based on structure-function studies of these classes of compounds. Imidazoquinoline-based TLR7/8 agonists are the most potent, but when used as a vaccine adjuvant side effects can arise due to diffusion from the injection site into a systemic circulation. In this work, we sought to address this issue through structural modifications in the agonists to enhance their adsorption capacity to the classic adjuvant alum. We selected a potent TLR7-selective agonist, BBIQ (EC50 = 0.85 μM), and synthesized polyphenolic derivatives to assess their TLR7 agonistic activity and adjuvant potential alone or in combination with alum. Most of the phenolic derivatives were more active than BBIQ and, except for 12b, all were TLR7 specific. Although the synthesized compounds were less active than resiquimod, the immunization data on combination with alum, specifically the IgG1, IgG2b and IgG2c responses, were superior in comparison to BBIQ as well as the reference standard resiquimod. Compound 12b was 5-fold more potent (EC50 = 0.15 μM in TLR7) than BBIQ and induced double the IgG response to SARS-CoV-2 and hepatitis antigens. Similarly, compound 12c (EC50 = 0.31 μM in TLR7) was about 3-fold more potent than BBIQ and doubled the IgG levels. Even though compound 12d exhibited low TLR7 activity (EC50 = 5.13 μM in TLR7), it demonstrated superior adjuvant results, which may be attributed to its enhanced alum adsorption capability as compared with BBIQ and resiquimod. Alum-adsorbed polyphenolic TLR7 agonists thereby represent promising combination adjuvants resulting in a balanced Th1/Th2 immune response.

Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor

The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic.

Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

In vitro and in silico anticancer potential of binuclear silver (I) N-heterocyclic carbene (NHCs) complexes: Investigation of interaction with surfactants

N-heterocyclic carbene (NHCs) silver complexes are getting tremendous attention for appealing biological potentials. The present study is planned to synthesize silver-NHC complexes to investigate their anticancer potential against breast, colon and ovarian cancer cell lines. The synthesized benzimidazolium salts (C1-C2) and their binuclear silver complexes (C3-C4) were assured through spectroscopy (UV–visible, FTIR, NMR and FLR), HPLC-DAD (high performance liquid chromatography), elemental analysis as well as mass spectrometry. Molecular docking studies indicated that compound C4 has lower binding energy values of −4.49, −1.95 and −2.95 kcal/mol for Bruton’s tyrosine kinase, Human topoisomerase II alpha and Aromatase cytochrome P450 protein targets respectively. The In Vitro cytotoxicity assay confirmed the C4 is better cytotoxic agent from other studied compounds of present study having lower IC50 values of 0.996 ± 0.04, 0.97 5 ± 0.04, 0.872 ± 0.05 and 0.987 ± 0.05 µg/mL against MCF-7, A-549, A-2780 and HCT-116 cell lines. Stability of compounds in solution form studied through spectroscopy and all compounds were found stable for studied course of time. Interactions of C3-C4 with surfactants (SDS, tween-20, tween-80) have confirmed the substantial interaction to improve aqueous solubility. Interaction of C3-C4 with surfactants indicates that there is potential affinity among test compounds and surfactants for complex formation spontaneously, having strongest binding affinity for SDS (sodium dodecyl sulfate) as compared to Tween-20 and Tween-80.

Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities

Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor—momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.

Pyrazole-thiazole hybrids: Synthesis, computational studies and impact on digestive enzymes

In this study, the syntheses of some pyrazole-thiazole hybrids and their cyanoacrylate derivatives have been reported. 1H NMR, 13C NMR, LC-MS, and IR spectroscopy were used to characterize all the synthesized compounds. DFT studies have been employed to assess the electronic properties of the synthesized compounds. To ensure the necessary metabolization of the synthesized compounds, their safety profiles were assessed using the Vnn-ADMAT tool. Docking studies investigated the interactions between the synthesized compounds (6a-h and 8a-h) and the active sites of gastric enzymes α-Amylase, Trypsin, and Pepsin with binding affinities (kcal mol−1) ranging from 6.0 to 8.1, 6.7 to 8.5, and 7.7 to 8.6, respectively. Both pyrazole-thiazole hybrids and their cyanoacrylate derivatives demonstrated efficient anti-gastric activities. Varying levels of inhibition were observed among the analogs, such as compound 8f exhibiting the highest inhibitory activity at 61.93 % against α-Amylase at 10−7M, compound 6e showed best inhibition at 68.09 % against Trypsin at 10−7M, and compound 6c displayed remarkable inhibition at 69.51 % against Pepsin at 10−7M. The synthesized compounds exhibited selectivity for α-Amylase.

New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study.

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2(VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A(VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).

Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities.

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer.

Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. Compound 3c is a novel and promising compound against N. americanus in vivo.

Synthesis and Biological Evaluation of 3-(2-Benzoyl-4-chlorophenyl)-4H-spiro [indole-3,2-[1,3]thiazolidine]-2,4(1H)- dione Derivatives for Anti-tubercular and Antimicrobial Activities

Objectives: To synthesize a new scaff fold of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'-[1,3] thiazolidine]-2,4'(1H)-dione derivatives and to assess the compounds for anti-tubercular and antimicrobial activities. Methods : A new series of 3'-(2-Benzoyl-4-chlorophenyl)-4'H-spiro [indole-3,2'- [1,3] thiazolidine]-2,4'(1H)-dione derivatives were prepared by synthesizing schiff’s bases followed by condensing schiff base with 2-mercaptopropanoic acid in the presence of zinc chloride. Synthesized compounds were characterized by IR, NMR and Mass spectral data. Their antimicrobial, antitubercular and also docking simulations were evaluated. Findings : Compound 3c (floro substituent) showed potent activity against Mycobacterium tuberculosis H37Rv with MIC value of 3.125 µg/ml when compared with standard Isoniazid. Compound 3c, 3d and 3f displayed better antimicrobial activity against used bacterial and fungal species with MIC range of 3-20µg/ml comparable to standard drugs ciprofloxacin and ketoconazole respectively. In silico studies revealed that compound 3c, 3f and 3d had a better binding affinity with M. tuberculosis enoyl-CoA hydratase EchA6 with ΔG values of -9.6kcal/mol, -9.4kcal/mol, and -8.6kcal/mol respectively comparable to isoniazid of -5.4kcal/mol. Compound 3c, 3f and 3d also displayed good binding affinity with DNA gyrase and lanosterol methylase. Novelty : Introducing benzoyl moiety to the thiazolidine ring potentiates the antitubercular and antimicrobial activity of spiro indole derivatives. Keywords: AntiTB, Antimicrobial, Molecular Docking, Spiro indole, Thiazolidine

Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.

There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

Crystal structure, DFT calculation, molecular docking, in vitro biological activity evaluation and in silico drug-likeness prediction of N-((1H-indol-3-yl)methyl)-4-(piperidin-1-yl)aniline

In the thesis, a novel compound named N-((1H-indol-3-yl)methyl)-4-(piperidin-1-yl)aniline (compound C3) targeting Mycobacterium tuberculosis cyt-bd oxidase was synthesized and crystallized. Compound C3 exhibited significant activity against cyt-bd oxidase, with IC50 values of 26.63 ± 0.2 μM, and also demonstrated efficacy against MtbH37Ra, with MIC values of 16.28 ± 0.2 μM. Therefore, further research was carried out to explore the molecular structure of compound C3 and its interaction with cyt-bd oxidase. Firstly, quantum chemical calculations were carried out to predict various spectral properties of C3 including structural optimization, infrared, Raman, 1H NMR and 13C NMR. In addition, Hirshfeld surface analysis is used to clarify the multiple interactions of C3, while two-dimensional fingerprints can accurately quantify the intermolecular interactions. Molecular electrostatic potential (MEP) is used to determine the sites where electrostatic interactions can be formed. Furthermore, FMOs (Frontier Molecular Orbitals) were utilized to assess the chemical stability of C3. Finally, molecular docking research was carried out to study the detailed interactions between cyt-bd oxidase and compound C3. In addition, ADME (absorption, distribution, metabolism and excretion) predictions show that compound C3 has good drug-forming and pharmacokinetics characteristics.