Sulphonamide Derivatives Research Articles

Computational Analysis and Inhibition Study of Carbonic Anhydrase from Azadirachta indica Leaves

Introduction: Carbonic anhydrase (CA) has been an enzyme of great interest for its application in carbon dioxide sequestration. A total of 66 protein sequences of plant CAs were computationally analyzed and submitted to bioinformatics for motif and domain identification, multiple sequence alignment, and phylogenetic analysis. Method: The current work aims to extend knowledge among researchers in better understanding the structure of AZDI CA by analyzing its physicochemical properties, secondary structure prediction, 3D modeling of protein sequence, and its validation using a variety of conventional computational methods. Results: The accuracy of the predicted 3D structure checked by the Ramachandran plot generated by PROCHECK showed that for the CA protein sequence 93.1%, was observed in the most favored regions, VERIFY 3D 69.44% and ERRAT 98.09%. AZDI CA was docked with various anions and sulphonamide derivatives to study their inhibitory effect and calculate binding energy by using Autodock 4.2. Ethoxzolamide is found to be a better inhibitor of AZDI CA with binding energy -8.71 kCal/mol and KI value 0.0004 mM. Further MD simulation of the docked complex of ethoxzolamide with AZDI CA was done using SCHRODINGER DESMOND software. Conclusion: The outcomes of this research will have a significant influence on biochemistry, biotechnology, and potential applications of AZDI CA and similar plant CAs in determining potent inhibitors for drug targets in treating various diseases.

Structure based exploration of mitochondrial alpha carbonic anhydrase inhibitors as potential leads for anti-obesity drug development.

Obesity has emerged as a major health challenge globally in the last two decades. Dysregulated fatty acid metabolism and de novo lipogenesis are prime causes for obesity development which ultimately trigger other co-morbid pathological conditions thereby risking life longevity. Fatty acid metabolism and de novo lipogenesis involve several biochemical steps both in cytosol and mitochondria. Reportedly, the high catalytically active mitochondrial carbonic anhydrases (CAVA/CAVB) regulate the intercellular depot of bicarbonate ions and catalyze the rapid carboxylation of pyruvate and acetyl-co-A to acetyl-co-A and malonate respectively, which are the precursors of fatty acid synthesis and lipogenesis. Several in vitro and in vivo investigations indicate inhibition of mitochondrial carbonic anhydrase isoforms interfere in the functioning of pyruvate, fatty acid and succinate pathways. Targeting of mitochondrial carbonic anhydrase isoforms (CAVA/CAVB) could thereby modulate gluconeogenetic as well as lipogenetic pathways and pave way for designing of novel leads in the development pipeline of anti-obesity medications. The present review unveils a diverse chemical space including synthetic sulphonamides, sulphamates, sulfamides and many natural bioactive molecules which selectively inhibit the mitochondrial isoform CAVA/CAVB with an emphasis on major state-of-art drug design strategies. More than 60% similarity in the structural framework of the carbonic anhydrase isoforms has converged the drug design methods towards the development of isoform selective chemotypes. While the benzene sulphonamide derivatives selectively inhibit CAVA/CAVB in low nanomolar ranges depending on the substitutions on the phenyl ring, the sulpamates and sulpamides potently inhibit CAVB. The virtual screening and drug repurposing methods have also explored many non-sulphonamide chemical scaffolds which can potently inhibit CAVA. The review could pave way for the development of novel and effective anti-obesity drugs which can modulate the energy metabolism.

Topiramate induced bilateral angle closure with anterior uveitis – A masquerade in a migraine patient

Topiramate (TPM), a sulphonamide derivative, is a commonly used medication by physicians and psychiatrists. Topiramate-induced angle closure glaucoma (ACG) and TPM-induced myopic shift are reported ocular adverse reactions of this drug. We report here a case of TPM-induced ciliochoroidal effusion presenting as bilateral acute angle closure with anterior uveitis and myopic shift in a patient with migraine. The acute and often bilateral severe visual deterioration in patients on TPM therapy cannot only be disturbing to the patient but can also be a challenge to the attending ophthalmologist to manage. We highlight the confusing presentation leading to the initial misdiagnosis of bilateral ACG and challenges in the management of this potentially sight-threatening condition.

Preparation, Characterization, In silico and In vitro Antimicrobial Studies of Phenothiazine-3-sulphonamide Derivatives

The antibacterial activities of phenothiazine and sulphonamide derivatives have attracted so much interest. In this study, the synthesis and characterization of phenothiazine-3-sulphonamide derivatives and evaluation of their antimicrobial activity against the following pathogenic microorganisms is reported. Two Gram-positive bacteria; (Staphylococcus aureus (ATCC: 6538) and Streptococcus pyogenes (ATCC: 27853)), two Gram-negative bacteria; (Escherichia coli(ATCC: 3008), and Salmonella typhi (ATCC: 25175)) as well as one fungus (Aspergillus fumigatus (ATCC: 10231)) were used while ciprofloxacin, gentamycin and ketoconazole served as standard drugs. The synthesis of the derivatives was achieved through a base catalyzed the reaction of 4-chloroaniline with 1-naphthylamine to form 1-(naphthalen-1-yl)benzene-1,4-diamine. This intermediate was then treated with sulphur and iodine to yield the phenothiazine derivative while subsequent treatment of the phenothiazine compound with sulphonyl chlorides gave the final products. The synthesized compounds were characterized via proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR) and Fourier-transform infrared (FTIR) spectroscopic techniques. The minimum inhibitory concentration (MIC) of each compound was then determined using the agar well diffusion method. To predict the binding energies and patterns of the synthesized compounds with target proteins of the above-mentioned microorganisms, molecular docking simulations were run using Autodock Vina software (version 4.2). The spectra data of the compounds for FTIR, 1H-NMR and 13C-NMR spectral data were consistent with the assigned structures of the synthesized compounds. The binding energies (kcal/mol) for in silico antimicrobial studies were in the range -5.1 to -7.6 kcal/mol. The MIC values were in the range 3.5 to 1.0 mg/L. The results of the in vitro test revealed that the synthesized compounds exhibit promising antimicrobial activity and showed excellent bactericidal and fungicidal activities. The results obtained showed that the synthesized compounds possess drug-like properties and are good starting materials for drug production.

Photophysical and antitubercular studies on newly synthesised structurally architectured sulphonamide

This study presents the synthesis and characterisation of four mono-azo sulphonamide derivatives through diazo-coupling electrophilic substitution reactions. The structural analysis of the synthesised molecules was conducted utilising FT-IR, 1H-NMR and HR-MS techniques. Absorption and fluorescence maxima of the synthesised molecules were determined across solvents of varying polarity to explore Solvatochromic behaviour. Density functional theory was employed to elucidate electronic and optical properties, including the computation of HOMO–LUMO energies using Gaussian 09W software, with comparisons to experimental data. Molecular electrostatic potential 3D plots identified electrophilic and nucleophilic sites. Solvent interactions were evaluated using Kamlet–Abboud Taft and Catalan parameters. Further, global chemical reactivity descriptors were estimated to ascertain chemical reactivity of the molecules. Additionally, the effectiveness of the colourant anti-tubercular activity was evaluated using in vitro and molecular docking techniques. The biological activity results reveal that methyl-pyridone and barbituric acid coupled with sulphamethizole (SMP and SMB) displayed excellent anti-tubercular activity compared with the standard Gentamycin.

Design, Synthesis, DFT, docking Studies, and antimicrobial evaluation of novel benzimidazole containing sulphonamide derivatives

In silico approaches have been employed to design a new series of benzimidazole-containing sulphonamide derivatives and qualified compounds have been synthesized to analyze their potential as antimicrobial agents. Antibacterial screening of all synthesized compounds was done using the broth microdilution method against several human pathogenic bacteria, viz. Gram-positive bacteria [B. cerus (NCIN-2156), B. subtilis (ATCC-6051), S. aureus (NCIM-2079)] and Gram-negative bacteria [P. aeruginosa (NCIM-2036), E. coli (NCIM-2065), and a drug-resistant strain of E. coli (U-621)], and the compounds presented admirable MIC values, ranging between 100–1.56 µg/mL. The combinatorial analysis showed the magnificent inhibitory efficiency of the tested compounds, acquired equipotent to ten-fold more potency compared to original MIC values. An immense synergistic effect was exhibited by the compounds during combination studies with reference drugs chloramphenicol and sulfamethoxazole was presented as fractional inhibitory concentration (∑FIC). Enzyme inhibition studies of all synthesized compounds were done by using peptidyl transferase and dihydropteroate synthase enzymes isolated from E. coli and S. aureus and each of the compound presented the admirable IC50 values, where the lead compound 3 bound to peptidyl transferase (of S. aureus with IC50 363.51 ± 2.54 µM and E. coli IC50 1.04 ± 0.08 µM) & dihydropteroate synthase (of S. aureus IC50 3.51 ± 0.82 µM and E. coli IC50 2.77 ± 0.65 µM), might account for the antimicrobial effect, exhibited excellent inhibition potential. Antifungal screening was also performed employing food poisoning methods against several pathogenic fungal species, viz A. flavus, F. oxysporum, A. niger, and A. brassicae. The obtained result indicated that few compounds can prove to be a potent drug regimen against dreaded MDR strains of microbes. Structural activity relationship (SAR) analysis and docking studies reveal that the presence of electron-withdrawing, polar, and more lipophilic substituents positively favor the antibacterial activity, whereas, electron-withdrawing, more polar, and hydrophilic substituents favor the antifungal activities. A robust coherence has been found in in-silico and in-vitro biological screening results of the compounds.

The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.

Synthesis and anticancer activity of cinnoline sulphonamides and 4‐heteroyclic derivatives: Cross‐coupling approach

AbstractA series of novel cinnoline sulphonamide derivatives and 4‐substuted cinnoline derivatives (13a‐h, 16a‐h and 17–31 total 33 analogues) were designed based on scaffold hopping techniques and evaluated for their antileukemic activity on wild type K562 as well as imatinib resistant cell lines (K562‐IR1 and K562‐IR2). Out of 33 analogues, five compounds (19, 22, 23, 28, and 31) exhibited potent antileukemic activity. An easy and efficient approach to synthesize numerous cinnoline derivatives by the various cross‐coupling reactions of 4‐chlorocinnoline has been developed and also demonstrated that metal‐free cross couplings give high product yield compared with metal catalyzed cross couplings.

Design, synthesis, in vitro urease inhibitory potentials and in silico molecular docking study of benzimidazole bearing thiosemicarbazides/sulfonamide Analogues

The nickel-containing urease enzyme is responsible for the pathogenesis of hepatic coma, hepatic encephalopathy, urolithiasis, gastric and peptic ulcer. These enzymes also have a negative effect on the efficacy of soil nitrogen to produce crops. The urease enzyme inhibitors may be thought as a strategy for reducing the negative effects of ureolytic bacteria. The present study involves a novel approach to the synthesis benzimidazole thiosemicarbazides and sulphonamide derivatives as potent urease inhibitor. All the analogues exhibited good inhibition potential. Among the thiosemicarbazides series, the most potent were analogs 1 g and 1 h having an IC50 = 2.40 ± 0.10 and 3.10 ± 0.10 µM respectively. Among the sulphonamide series, the most potent analogs were 2f and 2j having an IC50 = 3.90 ± 0.10 and 1.40 ± 0.001 µM respectively. Structure activity relationship study shows that among the two series, the most potent analogs were those having electron-withdrawing groups. Molecular docking study was carried out to check the interactions between the synthesized compounds and the urease enzyme's active sites. Furthermore, to evaluate the stability of the most active compound in complex with the urease enzyme a total of 200 ns MD simulation was carried out. The MD simulation study revealed that the compound formed a more stable complex with the urease enzyme and remained stable throughout the 200 ns MD simulation. All Compounds were verified for cytotoxicity against 3T3 mouse fibroblast cell line and detected nontoxic.

In vitro Antidiabetic and Anticancer Activity of Some Novel Diazenyl Benzene Sulphonamide Derivatives

A series of novel 2-[(5-phenyl-1,3,4-thiadiazole-2-imino)substituted benzene]diazenyl benzene sulphonamide derivatives (VII)6-10 weresynthesized and FT-IR, 1H NMR, 13C NMR and GC-MS spectral data were used to investigate the structures of the synthesized sulphonamide derivatives. The antioxidant activity of 2-[(5-phenyl-1,3,4-thiadiazole-2-imino)substituted benzene]diazenyl benzene sulphonamide derivatives (VII)6-10 was done using DPPH technique. Compounds (VII)7 and (VII)9 displayed excellent antioxidant activity when compared to standard ascorbic acid. The in vitro antidiabetic activity on α-amylase and α-glucosidase studies indicated compound (VII)7 as promising inhibitor of α-amylase and α-glucosidase. The cytotoxic activity of the synthesized compound (VII)9 was tested against human colon (HCT-116), lung (A549), breast (MCF-7) cancer cell lines and fibroblast (L929) normal mouse lines. The results showed that compound (VII)9 has good cytotoxic activity.

Synthesis, Computational, and In Vitro Antimycobacterial Studies on Benzofuran based Sulphonamide Derivatives (Part II)

Synthesis, Computational, and In Vitro Antimycobacterial Studies on Benzofuran based Sulphonamide Derivatives (Part II)

Design, Synthesis, in Vitro and Molecular Dynamic Study of Antifungal Activity of the Alcoholic Extract of Sygysium aromaticum in Comparison to Some New Sulphonamide Derivatives

Five synthetic 2-Thiouracil-5-sulphonamides were evaluated as antifungal agents against the same fungal isolates. Their synergistic effect with clove extract was assessed in an attempt to formulate a potential combination therapy for the future. The goal was to evaluate whether thiouracil derivatives and clove extract can enhance antifungal activity against drug-resistant strains of locally isolated fungi. Both natural and synthetic samples were tested against fungal isolates including Geotrichum candidum, Alternaria alternata, Fusarium oxysporum, and Mucorhiemalis, which are responsible for infections in potato and tomato plants. Clove extract demonstrated varying potent wide-spectrum activity against all fungal isolates, while the effectiveness of thiouracil derivatives depended on their chemical structures. Compounds 3b and 3e exhibited the most potent antifungal activity and showed a broad spectrum of effectiveness. Compound 3d displayed moderate antifungal activity compared to clove extract, while compound 3a exhibited weaker activity and was inactive against F. oxysporum and G. candidum. Compound 3c displayed the weakest antifungal activity and was inactive against A. alternata, F. oxysporum, and G. candidum. Both clove extract and 3e demonstrated synergistic antifungal activity. Moreover, the combination of clove extract and 2-thiouracil-5-sulphonamides displayed variable antifungal activity, suggesting the potential for synergistic effects in their activity.

Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity

Design and synthesis of three novel series of aryl enaminones (3a–f and 5a–c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the “tail approach” strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a–c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2–63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.

Synthetic methodologies and pharmacological applications of sulphonamide containing Schiff bases and their metal complexes: A comprehensive review

Schiff bases are useful chemical compounds with a wide range of applications. The Schiff bases are synthesized via the condensation reaction between carbonyl compounds (aldehydes or ketones) and compounds having an amine group and the Schiff base is characterised by an imine or azomethine (-C=N-) group. These compounds are extensively used as ligands to form coordination complexes with metal ions and are widely utilized in the treatment of various ailments. Sulphonamides are biologically significant class of drug-like chemical derivatives due to their good oral absorption and urine excretion. Sulphonamides are widely used as antimicrobial, anti-inflammatory, anticancer and antiviral drugs in addition to acting as powerful Carbonic anhydrase hCA inhibitors, HIV protease inhibitors, anti-obesity and anti-thyroid agents because of their less poisonous, more reactive and cost-effective nature. Sulphonamide-based Schiff bases and their metal chelates have attracted the focus of researchers due to their broad range of pharmacological characteristics. In this review, various pharmacological uses of Schiff base metal complexes generated from sulphonamide derivatives are discussed.

Diversely N-substituted benzenesulfonamides dissimilarly bind to human carbonic anhydrases: crystallographic investigations of N-nitrosulfonamides

Carbonic anhydrases (CAs) are a zinc metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and proton, pivotal for a wide range of biological processes. CAs are involved in numerous pathologies and thus represent valuable drug targets in the treatments of several diseases such as glaucoma, obesity, tumour, neuropathic pain, cerebral ischaemia, or as antiinfectives. In the last two decades, several efforts have been made to achieve selective CA inhibitors (CAIs) employing different drug design approaches. However, N-substitutions on primary sulphonamide groups still remain poorly investigated. Here, we reported for the first time the co-crystallisation of a N-nitro sulphonamide derivative with human (h) CA II pointing out the binding site and mode of inhibition of this class of CAIs. The thorough comprehension of the ligand/target interaction might be valuable for a further CAI optimisation for achieving new potent and selective derivatives.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Thiophenyl-chalcone derivatives: Synthesis, antioxidant activity, FMO energies and molecular parameters

In this study, a series of thiophenyl-chalcones derivatives was synthesized and their DPPH and ABTS activities were evaluated. All thiophenyl-chalcones exhibited high antioxidant activity. Among them, 4e ((E)-5-(3-(4-(chlorosulfonyl)-3-hydroxyphenyl)-3-oxoprop-1-en-1-yl)thiophene-2-sulfonyl chloride) have higher ABTS activity (IC50 = 13.12 μM) than quercetin (IC50 = 15.49 μM), well-known as antioxidant agent and used as a standard. The structure-activity relationship results revealed that most of synthesized sulfonyl chloride derivatives (4a-e) have higher antioxidant activity than the sulphonamide derivatives (5a-c) and also 4d and 4e including hydroxyl group, exhibited the strongest antioxidant activity as expected. Additionally, the frontier molecular orbitals (FMOs) energies and molecular parameters of the synthesized molecules were calculated to support experimental results. The quantum chemical calculation results indicated that the strongest antioxidant compounds, in this study, had the lowest LUMO energies and the highest electronegativity, electron affinity and electrophilicity index.

Design, synthesis and anti-diabetic activity of piperazine sulphonamide derivatives as dipeptidyl peptidase-4 inhibitors

Type II diabetes (T2DM) is considered one of the most prevalent metabolic disorders in the world. It is known as insulin resistance and persistent hyperglycemia. Over the past decade, inhibition of the enzymatic dipeptidyl peptidase-4 (DPP-4) has indeed been demonstrated to be an efficient and safe intervention for type 2 diabetes. In order to develop innovative DPP-4 inhibitors, several in silico techniques including 3D-QSAR, molecular docking, in-silico toxicity has been performed to confirm a total of 18 novel piperazine and pyridine derivatives to be synthesized from many designed molecules. These molecules have indeed been docked onto the protein surface of the DPP-4 enzyme, and ADMET characteristics have also been generated in silico. The compounds were then developed and analysed using FT-IR. Then, these compounds were investigated for DPP-4 inhibition in vitro. The most promising compound 8h showed 27.32% inhibition at 10μmol L-1 concentration over DPP-4 so selected for further in-vivo anti-diabetic evaluation. Compound 8h decreased blood glucose excursion in a dose-dependent manner during the OGTT and STZ-induced glucose models in normal Albino Wistar rats. Low-dose streptozotocin-induced type 2 diabetes in Albino Wistar rats treated chronically for 21 days with compound 8h resulted in a reduction in serum glucose levels. This highlighted that 8h is a moderately strong and specific blockbuster molecule that can be structurally modified to boost its effectiveness and overall pharmacological profile as a DPP-4 inhibitor.

Probing the influence of alkyl chain length on the aggregation behaviour of some naphthalene sulphonamide derivatives through spectroscopic and microscopic studies

With an aim to understand the role of alkyl chain length in tuning the optical properties of the organic aggregates, several naphthalene sulphonamide derivatives with different alkyl chain lengths have been synthesized. Molecular systems are used to fabricate different aggregates. Aggregation behaviour of the systems has been investigated by exploiting spectroscopic and microscopic technique. Investigations have revealed that the aggregates formed by shorter alkyl chain containing derivatives exhibit blue-shifted absorption and emission (as compared to respective monomer) to form H-aggregate whereas longer alkyl chain containing derivatives exhibit red-shifted absorption and emission (as compared to respective monomer) to form J-aggregate.

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 μM, 0.21 μM, 0.99 μM and 2.99 μM as compared to Osimertinib with IC50 values with of 0.0042 μM, 0.04 μM, 0.92 μM and 2.67 μM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties.