Browsing by Author "Sundriyal, Sandeep"

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2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-β-lactamases
(Elsevier, 2022-10) Sundriyal, Sandeep
Bacterial resistance to β-lactam antibiotics caused by class B metallo-β-lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2-substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activity relationship (SAR) and molecular modeling studies were performed and implications for further inhibitor design are discussed.
Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii
(JEM, 2011-06) Sundriyal, Sandeep
Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, the apicoplast. The apicoplast is indispensable and an attractive drug target. The apicoplast is home to a 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for the synthesis of isoprenoid precursors. This pathway is believed to be the most conserved function of the apicoplast, and fosmidomycin, a specific inhibitor of the pathway, is an effective antimalarial. Surprisingly, fosmidomycin has no effect on most other apicomplexans. Using Toxoplasma gondii, we establish that the pathway is essential in parasites that are highly fosmidomycin resistant. We define the molecular basis of resistance and susceptibility, experimentally testing various host and parasite contributions in T. gondii and Plasmodium. We demonstrate that in T. gondii the parasite plasma membrane is a critical barrier to drug uptake. In strong support of this hypothesis, we engineer de novo drug-sensitive T. gondii parasites by heterologous expression of a bacterial transporter protein. Mice infected with these transgenic parasites can now be cured from a lethal challenge with fosmidomycin. We propose that the varied extent of metabolite exchange between host and parasite is a crucial determinator of drug susceptibility and a predictor of future resistance.
Basic Nitrogen (BaN) Is a Key Property of Antimalarial Chemical Space
(ACS, 2023-06) Sundriyal, Sandeep
Most antimalarials are based on basic N-heterocycles and possess amine functionalities. Despite this, the role of basic nitrogen (BaN) in antimalarial drug design has not been studied systematically. Our cheminformatics analysis indicates that BaN is an important feature of antimalarial space. We show that potent research antiplasmodials (RAP) and advanced-stage antimalarials (ASAMs) consistently show a higher BaN count (#BaN) compared to oral drugs. Similarly, BaN is often a vital feature of the hits obtained from phenotypic screenings despite the use of varied assay conditions. The literature review demonstrates that in several unrelated scaffolds, the addition of BaN results in enhanced antiplasmodial activity. In addition, potent antiplasmodials and HTS hits are bulky, lipophilic, and less polar and have a high aromatic ring count (#AR). This characterization of antimalarial space may be used to collate a focused compound collection to achieve higher hit rates in HTS, as shown retrospectively in this perspective.
Basic nitrogen (BaN): a ‘privileged element’ in medicinal chemistry
(Taylor & Francis, 2024-10) Sundriyal, Sandeep
Medicinal chemists continuously search for small molecules with ideal pharmacokinetic and pharmacodynamic (PKPD) profiles. This quest has resulted in several efforts to understand and define ‘druglikeness’ or ‘drug-like chemical space’. Favorable drug-living system interactions ultimately depend on a compound's chemical structure. Hence, studying patterns and correlations between compound structure and PKPD parameters to derive common denominators is an obvious strategy [Citation1]. Since the publication of ‘Lipinski’s rule of five’ [Citation2], our understanding of the correlation between druglikeness and different physicochemical properties has evolved. Consequently, several guidelines have been suggested for selecting ‘quality’ compounds to improve success rates in preclinical and clinical studies.
Conformational Polymorphism in Sulfonylurea Drugs: Electronic Structure Analysis
(ACS, 2010-08) Sundriyal, Sandeep
Quantum chemical calculations have been performed using HF, B3LYP, and MP2 methods on the model sulfonylurea PhSO2NHC(═O)NHMe to understand the conformational and tautomeric preferences. The results indicate that a conformer with intramolecular hydrogen bond SLU-1 (hitherto not considered) is more stable than the conformer SLU-2 (which is generally considered) for sulfonylureas. The energy difference between these two conformers is about 4 kcal/mol in the gas phase; however, the energy differences between the two rotamers become negligible in the solvent phase. Iminol tautomeric forms of sulfonylurea (which were also not studied until now) are only about 5−6 kcal/mol higher in energy as per both gas-phase and solvent-phase analyses, indicating easy accessibility of tautomeric states in sulfonylureas. Quantum chemical analysis has also been carried out on the possible dimeric structures of these three important isomers of sulfonylurea, and correlations have been made to the known crystal structures of polymorphic states of sulfonylurea drugs
Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase
(ACS, 2009-10) Sundriyal, Sandeep
1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20−100 μM (or 3.7−19 μg/mL).
Crystal structures of non-uracil ring fragments in complex with Mycobacterium tuberculosis uracil DNA glycosylase (MtUng) as a starting point for novel inhibitor design: A case study with the barbituric acid fragment
(Elsevier, 2023-10) Sundriyal, Sandeep
Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 μM) displaying ∼24-fold potency over the uracil ring
Curation and cheminformatics analysis of a Ugi-reaction derived library (URDL) of synthetically tractable small molecules for virtual screening application
(Springer, 2022-12) Sundriyal, Sandeep
Virtual screening (VS) is an important approach in drug discovery and relies on the availability of a virtual library of synthetically tractable molecules. Ugi reaction (UR) represents an important multi-component reaction (MCR) that reliably produces a peptidomimetic scaffold. Recent literature shows that a tactically assembled Ugi adduct can be subjected to further chemical modifications to yield a variety of rings and scaffolds, thus, renewing the interest in this old reaction. Given the reliability and efficiency of UR, we collated an UR derived library (URDL) of small molecules (total = 5773) for VS. The synthesis of the majority of URDL molecules may be carried out in 1–2 pots in a time and cost-effective manner. The detailed analysis of the average property and chemical space of URDL was also carried out using the open-source Datawarrior program. The comparison with FDA-approved oral drugs and inhibitors of protein–protein interactions (iPPIs) suggests URDL molecules are ‘clean’, drug-like, and conform to a structurally distinct space from the other two categories. The average physicochemical properties of compounds in the URDL library lie closer to iPPI molecules than oral drugs thus suggesting that the URDL resource can be applied to discover novel iPPI molecules. The URDL molecules consist of diverse ring systems, many of which have not been exploited yet for drug design. Thus, URDL represents a small virtual library of drug-like molecules with unexplored chemical space designed for VS. The structures of all molecules of URDL, oral drugs, and iPPI compounds are being made freely accessible as supplementary information for broader application.
Current Advances in Antifungal Targets and Drug Development
(Bentham Science, 2006) Sundriyal, Sandeep
Fungi are one of the most neglected pathogens apparent from the fact that the Amphotericin B, a polyene antibiotic, discovered way back in 1956 is still used as a gold standard for antifungal therapy. Past two decades have witnessed a dramatic rise in the incidences of life threatening systemic fungal infections. This can be ascribed to the increase in the number of immuno-compromised patients due to rise in HIV infected population, cancer chemotherapy and indiscriminate use of antibiotics. Majority of clinically used antifungals suffer from various drawbacks in terms of toxicity, efficacy and cost, and their frequent use has led to the emergence of resistant strains. Hence, there is a great demand for novel antifungals belonging to wide range of structural classes, selectively acting on novel targets with fewer side effects. This article aims at reviewing recent efforts made towards discovering novel antifungal drug targets and investigational molecules acting on them.
Design and synthesis of non-hydroxamate lipophilic inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR): in silico, in vitro and antibacterial studies
(RSC, 2024-08) Sundriyal, Sandeep
1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway operating in several pathogens, including Mycobacterium and Plasmodium. Since a DXR homologue is not present in humans, it is an important antimicrobial target. Fosmidomycin (FSM) and its analogues inhibit DXR function by chelating the divalent metal (Mn2+ or Mg2+) in its active site via a hydroxamate metal binding group (MBG). The latter, however, enhances the polarity of molecules and is known to display metabolic instability and toxicity issues. While attempts have been made to increase the lipophilicity of FSM by substituting the linker chain and prodrug approach, very few efforts have been made to replace the hydroxamate group with other lipophilic MBGs. We report a systematic in silico and experimental investigation to identify novel MBGs for designing non-hydroxamate lipophilic DXR inhibitors. The SAR studies with selected MBG fragments identified novel inhibitors of E. Coli DXR with IC50 values ranging from 0.29 to 106 μM. The promising inhibitors were also screened against ESKAPE pathogens and M. tuberculosis.
Design, synthesis and in vitro evaluation of primaquine and diaminoquinazoline hybrid molecules against the malaria parasite
(Wiley, 2025-01) Sundriyal, Sandeep; Roy, Aniruddha
In this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC50 135.20–398.80 nM) against all intra-erythrocytic stages of the drug-sensitive 3D7 strain, with significant potency enhancement compared to PQ alone (IC50 9370 nM). These hybrids were also potent at killing drug-resistant strains (Dd2, Dd2 R539T, IPC4912, CamWT C580Y, and 7G8) in the nanomolar range, with 11 f being the most effective compound (IC50 172.20–396.60 nM). Notably, for the first time, we present evidence that the DAQ-based compound 8 and its hybrids can inhibit β-hematin formation in vitro with potency (IC50 0.90–27.80 μM), suggesting hemozoin formation to be one of the potential targets of this series. Lastly, two hybrids with potent antiplasmodial activity were also found to be safe up to 10 μM against human HepG2 cells, suggesting the possibility of achieving host vs parasite selectivity with this series.
Development and experimental validation of a machine learning model for the prediction of new antimalarials
(Springer, 2025-01) Sundriyal, Sandeep
A large set of antimalarial molecules (N ~ 15k) was employed from ChEMBL to build a robust random forest (RF) model for the prediction of antiplasmodial activity. Rather than depending on high throughput screening (HTS) data, molecules tested at multiple doses against blood stages of Plasmodium falciparum were used for model development. The open-access and code-free KNIME platform was used to develop a workflow to train the model on 80% of data (N ~ 12k). The hyperparameter values were optimized to achieve the highest predictive accuracy with nine different molecular fingerprints (MFPs), among which Avalon MFPs (referred to as RF-1) provided the best results. RF-1 displayed 91.7% accuracy, 93.5% precision, 88.4% sensitivity and 97.3% area under the Receiver operating characteristic (AUROC) for the remaining 20% test set. The predictive performance of RF-1 was comparable to that of the malaria inhibitor prediction platform (MAIP), a recently reported consensus model based on a large proprietary dataset. However, hits obtained from RF-1 and MAIP from a commercial library did not overlap, suggesting that these two models are complementary. Finally, RF-1 was used to screen small molecules under clinical investigations for repurposing. Six molecules were purchased, out of which two human kinase inhibitors were identified to have single-digit micromolar antiplasmodial activity. One of the hits (compound 1) was a potent inhibitor of β-hematin, suggesting the involvement of parasite hemozoin (Hz) synthesis in the parasiticidal effect. The training and test sets are provided as supplementary information, allowing others to reproduce this work
Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-Stage Antimalarial Compounds
(Wiley, 2014-07) Sundriyal, Sandeep
Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1-benzyl-4-piperidyl)[6,7-dimethoxy-2-(4-methyl-1,4-diazepin-1-yl)-4-quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.
Discovery of small molecule inhibitors of Mycobacterium tuberculosis ClpC1: SAR studies and antimycobacterial evaluation
(Elsevier, 2023-01) Sundriyal, Sandeep
The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 µM. Investigation of the structure–activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.
Environmental sustainability and its impact on public health
(Springer, 2024-09) Sundriyal, Sandeep
This book chapter provides a comprehensive review of the relationship between environmental sustainability and public health. It explores the various environmental factors that affect public health, discusses the pathways through which these factors impact human well-being, and highlights the potential benefits of environmental sustainability initiatives in improving public health outcomes. The chapter presents case studies and examples of successful interventions, identifies challenges and barriers to achieving environmental sustainability, and offers recommendations for promoting sustainable practices to enhance public health. In this chapter, the intersection of environmental sustainability and public health has been explored, highlighting the interdependencies and impacts between the two. A holistic and interconnected approach is needed to address environmental and health challenges. For improved acceptance, implementation, and environmental sustainability, it is advised to translate or disseminate research-based solutions into practice.
Harnessing antimalarial chemical space: the way forward
(Taylor & Francis, 2025-10) Sundriyal, Sandeep
Malaria remains a major health challenge, with increasing resistance to frontline chemotherapy. Recent cheminformatics studies have revealed that potent antiplasmodials occupy a distinct antimalarial chemical space (AMCS), defined by specific property cutoffs.
Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity
(RSC, 2017-03) Sundriyal, Sandeep
Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites). However, future development of this series will need to address host versus parasite selectivity, where inhibitory activity against human G9a is removed from the lead compounds, while maintaining potent anti-Plasmodium activity. Herein, we report an extensive study of the SAR of this series against both G9a and P. falciparum. We have identified key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved by selecting appropriate substituents at position 2, 4 and 7 of the quinazoline ring. We have also, in turn, discovered that potent G9a inhibitors can be identified by employing a 6-carbon ‘Nle mimic’ at position 7. Together, this data suggests that while broadly similar, the G9a and potential PfHKMT target(s) binding pockets and/or binding modes of the diaminoquinazoline analogues exhibit clear and exploitable differences. Based on this, we believe this scaffold to have clear potential for development into a novel anti-malarial therapeutic.
Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans
(ASM Journals, 2015-01) Sundriyal, Sandeep
Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Histone methyltransferase inhibitors: orally bioavailable, fast acting molecules with activity against different human malaria species
(OUP, 2014) Sundriyal, Sandeep
Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity with IC50 values <50 nM against drug sensitive laboratory strains and multi-drug resistant field isolates including artemisinin refractory P. falciparum isolates. Activity against ex vivo clinical isolates of both P. falciparum and P. vivax were similar with potencies of 300-400 nM. Sexual stage gametocyte inhibition occurs at micromolar levels, however, mature gametocyte progression to gamete formation is inhibited at sub-micromolar concentrations. Parasite reduction ratio analysis confirms a fast asexual stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of P. berghei and P. falciparum infection. The discovery of a rapid and broad-acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitor
(RSC, 2014-08) Sundriyal, Sandeep
G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data.