Browsing by Author "Kumar, Gautam"

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Biaryl carboxamide-based peptidomimetics analogs as potential pancreatic lipase inhibitors for treating obesity
(Wiley, 2024-01) Kumar, Gautam; Paul, Atish Tulshiram
A series of 1,1′-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry techniques. The synthesized peptidomimetics analogs were screened in vitro to understand the inhibitory potential of pancreatic lipase (PL). Analogs were assessed for the PL inhibitory activity based on interactions, geometric complementarity, and docking score. Among the synthesized analogs, 9, 29, and 24 were found to have the most potent PL inhibitory activity with IC50 values of 3.87, 4.95, and 5.34 µM, respectively, compared to that of the standard drug, that is, orlistat, which inhibits PL with an IC50 value of 0.99 µM. The most potent analog, 9, exhibited a competitive-type inhibition with an inhibition constant (Ki) of 2.72 µM. In silico molecular docking of analog 9 with the PL (PDB ID:1LPB) showed a docking score of −11.00 kcal/mol. Analog 9 formed crucial hydrogen bond interaction with Ser152, His263, π–cation interaction with Asp79, Arg256, and π–π stacking with Phe77, Tyr114 at the protein's active site. The molecular dynamic simulation confirmed that analog 9 forms stable interactions with PL at the end of 200 ns with root mean square deviation values of 2.5 and 6 Å. No toxicity was observed for analog 9 (concentration range of 1–20 µM) when tested by MTT assay in RAW 264.7 cells.
Cancer multidrug-resistance reversal by abcb1 inhibition: a recent update
(Elsevier, 2022-09) Kumar, Gautam
Chemotherapy is one of the most common treatments for cancer that uses one or more anti-cancer drugs as a part of the standardized chemotherapy regimen. Cytotoxic chemicals delay and prevent cancer cells from multiplying, invading, and metastasizing. However, the significant drawbacks of cancer chemotherapy are the lack of selectivity of the cytotoxic drugs to tumour cells and normal cells and the development of resistance by cells for the particular drug or the combination of drugs. Multidrug resistance (MDR) is the low sensitivity of specific cells against drugs associated with cancer chemotherapy. The most common mechanisms of anticancer drug resistance are: (a) drug-dependent MDR (b) target-dependent MDR, and (c) drug target-independent MDR. In all the factors, the overexpression of multidrug efflux systems contributes significantly to the increased resistance in the cancer cells. Multidrug resistance due to efflux of anticancer drugs by membrane ABC transporters includes ABCB1, ABCC1, and ABCG2. ABCB1 inhibition can restore the sensitivity of the cancerous cells toward chemotherapeutic drugs. In this review, we discussed ABCB1 inhibitors under clinical studies with their mode of action, potency and selectivity. Also, we have highlighted the contribution of repurposing drugs, biologics and nano formulation strategies to combat multidrug resistance by modulating the ABCB1 activity.
Chemical tools for illumination of tuberculosis biology, virulence mechanisms, and diagnosis
(ACS, 2020-12) Kumar, Gautam
Tuberculosis (TB) remains one of the deadliest infectious diseases and begs the scientific community to up the ante for research and exploration of completely novel therapeutic avenues. Chemical biology-inspired design of tunable chemical tools has aided in clinical diagnosis, facilitated discovery of therapeutics, and begun to enable investigation of virulence mechanisms at the host–pathogen interface of Mycobacterium tuberculosis. This Perspective highlights chemical tools specific to mycobacterial proteins and the cell lipid envelope that have furnished rapid and selective diagnostic strategies and provided unprecedented insights into the function of the mycobacterial proteome and lipidome. We discuss chemical tools that have enabled elucidating otherwise intractable biological processes by leveraging the unique lipid and metabolite repertoire of mycobacterial species. Some of these probes represent exciting starting points with the potential to illuminate poorly understood aspects of mycobacterial pathogenesis, particularly the host membrane–pathogen interactions.
Efflux pump inhibitory potential of indole derivatives as an arsenal against norA over-expressing Staphylococcus aureus
(ASM, 2023-09) Kumar, Gautam
NorA, an extensively studied efflux pump in Staphylococcus aureus, has been connected to fluoroquinolone, antiseptic, and disinfection resistance. Several studies have also emphasized how efflux pumps, including NorA, function as the first line of defense of S. aureus against antibiotics. In this study, we have screened some chemically synthesized indole derivatives for their activity as efflux pump inhibitors (EPIs). The derivative SMJ-5 was found to be a potent NorA efflux pump inhibitor among the screened indole derivatives, owing to increased ethidium bromide and norfloxacin accumulation in norA over-expressing S. aureus. The combination of SMJ-5 and ciprofloxacin demonstrated the eradication of S. aureus biofilm and prolonged the post-antibiotic effect more than ciprofloxacin alone. SMJ-5 was able to inhibit staphyloxanthin virulence. In in vitro time-kill trials and in vivo efficacy investigations, the combination enhanced the bactericidal activity of ciprofloxacin against S. aureus. Additionally, reverse transcription PCR results revealed that SMJ-5 also inhibits the NorA efflux pump indirectly at the transcriptional level.
Enhancing cancer immunotherapy: Exploring strategies to target the PD-1/PD-L1 axis and analyzing the associated patent, regulatory, and clinical trial landscape
(Elsevier, 2024-07) Kumar, Gautam
Cancer treatment modalities and their progression is guided by the specifics of cancer, including its type and site of localization. Surgery, radiation, and chemotherapy are the most often used conventional treatments. Conversely, emerging treatment techniques include immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy. Immune checkpoint inhibitors’ anticancer properties have drawn considerable attention in recent studies in the cancer research domain. Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) checkpoint pathway are key regulators of the interactions between activated T-cells and cancer cells, protecting the latter from immune destruction. When the ligand PD-L1 attaches to the receptor PD-1, T-cells are prevented from destroying cells that contain PD-L1, including cancer cells. The PD-1/PD-L1 checkpoint inhibitors block them, boosting the immune response and strengthening the body’s defenses against tumors. Recent years have seen incredible progress and tremendous advancement in developing anticancer therapies using PD-1/PD-L1 targeting antibodies. While immune-related adverse effects and low response rates significantly limit these therapies, there is a need for research on methods that raise their efficacy and lower their toxicity. This review discusses various recent innovative nanomedicine strategies such as PLGA nanoparticles, carbon nanotubes and drug loaded liposomes to treat cancer targeting PD-1/PD-L1 axis. The biological implications of PD-1/PD-L1 in cancer treatment and the fundamentals of nanotechnology, focusing on the novel strategies used in nanomedicine, are widely discussed along with the corresponding guidelines, clinical trial status, and the patent landscape of such formulations
Identification and benchmarking of myokinasib-ii as a selective and potent chemical probe for exploring mlck1 inhibition
(ACS, 2024-09) Kumar, Gautam
Deciphering the functional relevance of every protein is crucial to developing a better (patho)physiological understanding of human biology. The discovery and use of quality chemical probes propel exciting developments for developing drugs in therapeutic areas with unmet clinical needs. Myosin light-chain kinase (MLCK) serves as a possible therapeutic target in a plethora of diseases, including inflammatory diseases, cancer, etc. Recent years have seen a substantial increase in interest in exploring MLCK biology. However, there is only one widely used MLCK modulator, namely, ML-7, that too with a narrow working concentration window and high toxicity profile leading to limited insights. Herein, we report the identification of a potent and highly selective chemical probe, Myokinasib-II, from the synthesis and structure–activity relationship studies of a focused indotropane-based compound collection. Notably, it is structurally distinct from ML-7 and hence meets the need for an alternative inhibitor to study MLCK biology as per the recommended best practices. Moreover, our extensive benchmarking studies demonstrate that Myokinasib-II displays better potency, better selectivity profile, and no nonspecific interference in relevant assays as compared to other known MLCK inhibitors.
Microemulsions, nanoemulsions and emulgels as carriers for antifungal antibiotics
(Taylor & Francis, 2023-11) Kumar, Gautam
According to estimates, up to 25% of the world’s population has fungal skin diseases, making them the most prevalent infectious disease. Several chemical classes of antifungal drugs are available to treat fungal infections. However, the major challenges of conventional formulations of antifungal drugs include poor pharmacokinetic profiles like solubility, low permeability, side effects and decreased efficacy. Novel drug delivery is a promising approach for overcoming pharmacokinetic limitations and increasing the effectiveness of antibiotics. In this review, we have shed light on microemulsions, nanoemulsions, and emulgels as novel drug delivery approaches for the topical delivery of antifungal antibiotics. We believe these formulations have potential translational value and could be developed for treating fungal infections in humans.
Natural peptides and their synthetic congeners acting against Acinetobacter baumannii through the membrane and cell wall: latest progress
(RSC, 2024-11) Kumar, Gautam
Acinetobacter baumannii is one of the deadliest Gram-negative bacteria (GNB), responsible for 2–10% of hospital-acquired infections. Several antibiotics are used to control the growth of A. baumannii. However, in recent decades, the abuse and misuse of antibiotics to treat non-microbial diseases have led to the emergence of multidrug-resistant A. baumannii strains. A. baumannii possesses a complex cell wall structure. Cell wall-targeting agents remain the center of antibiotic drug discovery. Notably, the antibacterial drug discovery intends to target the membrane of the bacteria, offering several advantages over antibiotics targeting intracellular systems, as membrane-targeting agents do not have to travel through the plasma membrane to reach the cytoplasmic targets. Microorganisms, insects, and mammals produce antimicrobial peptides as their first line of defense to protect themselves from pathogens and predators. Importantly, antimicrobial peptides are considered potential alternatives to antibiotics. This communication summarises the recently identified peptides of natural origin and their synthetic congeners acting against the A. baumannii membrane by cell wall disruption.
Natural products acting against S. aureus through membrane and cell wall disruption
(RSC, 2023-06) Kumar, Gautam
Staphylococcus aureus (S. aureus) is responsible for several community and hospital-acquired infections with life-threatening complications such as bacteraemia, endocarditis, meningitis, liver abscess, and spinal cord epidural abscess. In recent decades, the abuse and misuse of antibiotics in humans, animals, plants, and fungi and the treatment of nonmicrobial diseases have led to the rapid emergence of multidrug-resistant pathogens. The bacterial wall is a complex structure consisting of the cell membrane, peptidoglycan cell wall, and various associated polymers. The enzymes involved in bacterial cell wall synthesis are established antibiotic targets and continue to be a central focus for antibiotic development. Natural products play a vital role in drug discovery and development. Importantly, natural products provide a starting point for active/lead compounds that sometimes need modification based on structural and biological properties to meet the drug criteria. Notably, microorganisms and plant metabolites have contributed as antibiotics for noninfectious diseases. In this study, we have summarized the recent advances in understanding the activity of the drugs or agents of natural origin that directly inhibit the bacterial membrane, membrane components, and membrane biosynthetic enzymes by targeting membrane-embedded proteins. We also discussed the unique aspects of the active mechanisms of established antibiotics or new agents.
Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update
(Wiley, 2023-04) Kumar, Gautam
Tuberculosis (TB) remains one of the deadliest infectious diseases caused by Mycobacterium tuberculosis (M.tb). It is responsible for significant causes of mortality and morbidity worldwide. M.tb possesses robust defense mechanisms against most antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. Thus, the efficacy of existing front-line drugs is diminishing, and new and recurring cases of TB arising from multidrug-resistant M.tb are increasing. TB begs the scientific community to explore novel therapeutic avenues. A precise knowledge of the compounds with their mode of action could aid in developing new anti-TB agents that can kill latent and actively multiplying M.tb. This can help in the shortening of the anti-TB regimen and can improve the outcome of treatment strategies. Natural products have contributed several antibiotics for TB treatment. The sources of anti-TB drugs/inhibitors discussed in this work are target-based identification/cell-based and phenotypic screening from natural products. Some of the recently identified natural products derived leads have reached clinical stages of TB drug development, which include rifapentine, CPZEN-45, spectinamide-1599 and 1810. We believe these anti-TB agents could emerge as superior therapeutic compounds to treat TB over known Food and Drug Administration drugs.
Natural products and traditional herbal medicines as managerial therapies to combat rheumatoid arthritis
(Springer, 2024-03) Kumar, Gautam
Rheumatoid arthritis (RA) is a complex and challenging autoimmune disease characterized by chronic inflammation of the joints, discomfort, stiffness, functional impairment, and systemic complications that affect millions of people around the world. Despite advances in medication, controlling RA remains difficult due to its complicated pathophysiology and numerous clinical symptoms. Synthetic medications, while effective, frequently cause considerable adverse effects, necessitating the investigation of alternate therapeutic options. This study attempts to provide a complete overview of synthetic medications and natural items used to treat RA. It specifically investigates the pathophysiological mechanisms that underpin RA and the efficacy and safety profiles of synthetic pharmaceuticals. Synthetic medications, such as disease-modifying antirheumatic drugs (DMARDs), and biologics remain important treatments for RA, albeit with hazards. So to explore safer and more effective therapy for the treatment of RA, a need to exploit the possible therapeutic benefits of natural items such as antioxidants, plant secondary metabolites, and traditional herbal remedies arises. By encompassing a spectrum of insights, from the molecular level to holistic traditional practices, this review aims to provide a holistic understanding of the role of natural products and traditional herbal medicines in the managerial landscape of RA. Furthermore, it investigates the effect of nutrition in regulating inflammation and disease development in RA. Integrative techniques that use natural products present intriguing adjuvant therapy, delivering anti-inflammatory, analgesic, and immunomodulatory effects with potentially fewer side effects. Understanding the interaction of synthetic medications and natural products, as well as the role of nutrition, can help enhance RA treatment regimens, improve patient outcomes, and reduce treatment-related problems. This study is a valuable resource for doctors, researchers, and patients looking for evidence-based methods for RA care. The synthesis of this knowledge contributes to the ongoing pursuit of enhanced therapeutic strategies, fostering improved outcomes and quality of life for individuals grappling with rheumatoid arthritis
Naturally occurring organosulfur for treating metabolic disorders and infectious diseases
(Springer, 2024-11) Kumar, Gautam
Sulfur has been used as a medicinal agent by the Greeks since ancient times. Approximately 350 sulfur-containing compounds have been approved as drugs by the Food and Drug Administration (FDA). Generally, sulfur exists as organosulfur in plants and as glucosinolates and isothiocyanates. Metabolic disorders and infectious diseases are becoming worldwide public health problems, directly affecting individuals' quality of life and constitute a robust economic challenge to healthcare systems. Glucosinolates have been reported in several vegetables, bacteria, plants, fungi, and animals. In addition to organosulfur, glucosinolates, and their hydrolyzed products, isothiocyanates have immense therapeutic value. Several studies suggest glucosinolates have a potential role in treating metabolic disorders, including cancer, diabetes, and inflammation. Also, some of the glucosinolates had shown broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria and antifungal activity against fungal strains. This review discusses recently identified naturally occurring sulfur-containing compounds, including glucosinolates and organosulfur, and their therapeutic potential for treating metabolic disorders and infectious diseases.
Novel hydrazine derivatives as selective DPP-IV inhibitors: findings from virtual screening and validation through molecular dynamics simulations
(Springer, 2014-04) Kumar, Gautam
The present study demonstrates and validates the discovery of two novel hydrazine derivatives as selective dipeptidyl peptidase-IV (DPP-IV) inhibitors. Virtual screening (VS) of publicly available databases was performed using virtual screening workflow (VSW) of Schrödinger software against DPP-IV and the most promising hits were selected. Selectivity was further assessed by docking the hits against homology modeled structures of DPP8 and DPP9. Two novel hydrazine derivatives were selected for further studies based on their selectivity threshold. To assess their correct binding modes and stability of their complexes with enzyme, molecular dynamic (MD) simulation studies were performed against the DPP-IV protein and the results revealed that they had a better binding affinity towards DPP-IV as compared to DPP 8 and DPP 9. The binding poses were further validated by docking these ligands with different softwares (Glide and Gold). The proposed binding modes of hydrazines were found to be similar to sitagliptine and alogliptine. Thus, the study reveals the potential of hydrazine derivatives as highly selective DPP-IV inhibitors.
Pyrazole–coumarin and pyrazole–quinoline chalcones as potential antitubercular agents
(Wiley, 2020-06) Kumar, Gautam
Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study, two series of novel pyrazole–coumarin chalcones and pyrazole–quinoline chalcones were synthesized using multiple-step reactions. All the synthesized compounds were well characterized using different spectroscopic techniques including 1H and 13C nuclear magnetic resonance, high-resolution mass spectroscopy, and electrospray ionization–mass spectrometry. The compounds were evaluated for their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain using the microplate Alamar Blue assay, and the minimal inhibitory concentrations (MIC) of the compounds were determined. Among the 32 tested compounds, compounds 3e, 3u, and 7h showed an MIC value of 3.125 µg/ml, and they were found to be nontoxic. Molecular docking studies of the compounds with the enzyme DprE1 revealed the probable mechanism of action. The chalcone derivatives exhibited binding affinity values between −7.047 and −9.353 kcal/mol. ADME parameters were predicted using the QikProp module of the Schrödinger software, and these compounds exhibited good pharmacological and oral absorption properties.
Pyrazole-pyrazoline as promising novel antimalarial agents: a mechanistic study
(Elsevier, 2018-04) Kumar, Gautam
A series of pyrazole-pyrazoline substituted with benzenesulfonamide were synthesized and evaluated for their antimalarial activity in vitro and in vivo. The compounds were active against both chloroquine (CQ) sensitive (3D7) and CQ resistant (RKL-9) strains of Plasmodium falciparum. Seven compounds (7e, 7i, 7j, 7l, 7m, 7o and 7p) exhibiting EC50 less than 2 μM. A mechanistic study of compound 7o revealed that these compound act through the inhibition of β-hematin. The study indicated that these compounds can serve as lead compounds for further development of potent antimalarial drugs.
Synthesis and biological evaluation of dihydroquinoline carboxamide derivatives as anti-tubercular agents
(Elsevier, 2018-09) Kumar, Gautam
Sodium trifluoromethanesulfonate, and glacial acetic acid selectively catalyzed the synthesis of dihydroquinoline via Friedländer annulation. The synthesized dihydroquinoline analogues coupled with different amines by the use of coupling reagent gave dihydroquinoline carboxamide derivatives in moderate to good yields. All the synthesized novel compounds were evaluated for the anti-tubercular activity and cytotoxic activities in vitro. Among tested 30 compounds, two compounds, 8g and 8h showed MIC value of 0.39 and 0.78 μg/mL, respectively against Mycobacterium tuberculosis H37Rv and they were found to be non-toxic. Also these two compounds exhibited good pharmacological properties and oral absorption when studied using in-silico models.
Synthesis of carbohydrazides and carboxamides as anti-tubercular agents
(Elsevier, 2018-08) Kumar, Gautam
A novel series of furan/thiophene carbohydrazides and carboxamides were synthesized and evaluated for anti-TB and cytotoxic activities. All the synthesized compounds were characterized using 1H and 13C NMR and mass spectral techniques. Among the 23 compounds tested for anti-tubercular activity, seven compounds (3e, 3g, 3h, 9b, 9c, 9e and 9h) showed minimum inhibitory concentration value less than 1 μg/mL against Mycobacterium tuberculosis H37Rv and they were found to be non-toxic. Molecular docking and dynamics simulation studies of these compounds with an enzyme enoyl ACP reductase revealed the probable mechanism of action, which is similar to isoniazid. Further, all these tested compounds exhibited good absorption, distribution, metabolism and excretion and drug-likeness in-silico and thus may be considered as potential leads for further drug development.
Synthesis, biological evaluation and computational studies of acrylohydrazide derivatives as potential Staphylococcus aureus NorA efflux pump inhibitors
(Elsevier, 2020-11) Kumar, Gautam
The NorA efflux pump decreases the intracellular concentration of fluoroquinolones (ciprofloxacin, norfloxacin) by effluxing them from Staphylococcus aureus cells. The synthesis of novel acrylohydrazide derivatives was achieved using well-known reactions and were characterized by various spectroscopy techniques. The synthesized 50 compounds were evaluated for the NorA efflux pump inhibition activity against S. aureus SA-1199B (norA++) and K1758 (norA-) strains. The study provided two most active compounds viz. 19 and 52. Compound 19 was found to be most active in potentiating effect of norfloxacin and also it showed enhanced uptake, efflux inhibition in ethidium bromide assay. Further compound 19 also enhanced post antibiotic effect and reduced mutation prevention concentration of norfloxacin. The homology modeling study was performed to elucidate three-dimensional structure of NorA. Docking studies of potent molecules were done to find the binding affinity and interaction with active site residues. Further, all the tested compounds exhibited good ADME and drug-likeness properties in- silico. Based on the in-silico studies and detailed in vitro studies, acrylohydrazides derivatives may be considered as potential NorA EPI candidates.
Tackling Influenza A virus by M2 ion channel blockers: Latest progress and limitations
(Elsevier, 2024-03) Kumar, Gautam
Influenza outbreaks cause pandemics in millions of people. The treatment of influenza remains a challenge due to significant genetic polymorphism in the influenza virus. Also, developing vaccines to protect against seasonal and pandemic influenza infections is constantly impeded. Thus, antibiotics are the only first line of defense against antigenically distinct strains or new subtypes of influenza viruses. Among several anti-influenza targets, the M2 protein of the influenza virus performs several activities. M2 protein is an ion channel that permits proton conductance through the virion envelope and the deacidification of the Golgi apparatus. Both these functions are critical for viral replication. Thus, targeting the M2 protein of the influenza virus is an essential target. Rimantadine and amantadine are two well-known drugs that act on the M2 protein. However, these drugs acquired resistance to influenza and thus are not recommended to treat influenza infections. This review discusses an overview of anti-influenza therapy, M2 ion channel functions, and its working principle. It also discusses the M2 structure and its role, and the change in the structure leads to mutant variants of influenza A virus. We also shed light on the recently identified compounds acting against wild-type and mutated M2 proteins of influenza virus A. These scaffolds could be an alternative to M2 inhibitors and be developed as antibiotics for treating influenza infections.
Tackling multi-drug resistant fungi by efflux pump inhibitors
(Elsevier, 2024-08) Kumar, Gautam
The emergence of multidrug-resistant fungi is of grave concern, and its infections are responsible for significant deaths among immunocompromised patients. The treatment of fungal infections primarily relies on a clinical class of antibiotics, including azoles, polyenes, echinocandins, polyketides, and a nucleotide analogue. However, the incidence of fungal infections is increasing as the treatment for human and plant fungal infections overlaps with antifungal drugs. The need for new antifungal agents acting on different targets than known targets is undeniable. Also, the pace at which loss of fungal susceptibility to antibiotics cannot be undermined. There are several modes by which fungi can develop resistance to antibiotics, including reduced drug uptake, drug target alteration, and a reduction in the cellular concentration of the drug due to active extrusions and biofilm formation. The efflux pump’s overexpression in the fungi primarily reduced the antibiotic’s concentration to a sub-lethal concentration, thus responsible for developing resistant fungus strains. Several strategies are used to check antibiotic resistance in multi-drug resistant fungi, including synthesizing antibiotic analogs and giving antibiotics in combination therapies. Among them, the efflux pump protein inhibitors are considered potential adjuvants to antibiotics and can block the efflux of antibiotics by inhibiting efflux pump protein transporters. Moreover, it can sensitize the antifungal drugs to multi-drug resistant fungi with overexpressed efflux pump proteins. This review discusses the natural lead molecules, repurposable drugs, and formulation strategies to overcome the efflux pump activity in the fungi