Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Carvacrol-conjugated 3-Hydroxybenzoic Acids: Design, Synthesis, cardioprotective potential against doxorubicin-induced Cardiotoxicity, and ADMET study.

Carvacrol (CA) is a phenolic monoterpene renowned for its diverse pharmacological benefits, particularly its cardioprotective effects. Concurrently, phenolic acids have also demonstrated promise in mitigating drug-induced cardiotoxicity. Focusing on combating doxorubicin-induced cardiotoxicity (DIC), the research aims to synthesize novel cardioprotective agents by combining CA with 3-hydroxybenzoic acid (3HA). Doxorubicin, an anticancer drug, poses cardiovascular risks as its adverse effect, prompting the exploration of hybrid compounds. Various linker molecules, including alkyl and acyl with different carbon lengths, were investigated to understand their impact on bioactivity. In vitro testing on the DOX-induced H9c2 cell death model revealed the effectiveness of a CA conjugate in preserving cardiomyocyte viability. In silico analysis highlighted favorable drug-like properties and low toxicity of the conjugate. This study sheds light on molecular hybridization's potential in developing cardioprotective agents, emphasizing CA's pivotal role in combating DIC.

Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies.

In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds' selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 µg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability.

Synthesis, in vitro, and in silico studies of new derivatives of diphenylpiperazine scaffold: A key substructure for MAO inhibition.

Fifteen new diphenylpiperazine hybrids were designed, synthesized and in vitro biologically evaluated against hMAOs enzymes via fluorometric method. All of our new compounds displayed strong inhibitory activities against both two isoforms of hMAOs with IC50 range of 0.091-16.32 µM. According to selectivity index values, all hybrids showed higher selectivity against hMAO-A over hMAO-B. Compound 8 exhibited the best hMAO-A inhibition activity (IC50 value = 91 nM, SI = 19.55). With a selectivity index of 31.02 folds over MAO-B, compound 7 was revealed to be the most effective hMAO-A inhibitor. In silico prediction of physicochemical parameters and BBB permeability proved that all of the newly synthesized compounds have favorable pharmacokinetic profiles and acceptable ADME properties and can pass BBB. For clarification and explanation of the biological activity of compounds 7 and 8, molecular docking simulations were carried out. In light of this, 1,4-diphenylpiperazine analogues can be seen as an encouraging lead to develop safe and effective new drugs for treatment of many disorders such as anxiety and depression by inhibition of hMAO-A enzyme.

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy.

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.

Synthesis and evaluation of pentacyclic triterpenoids conjugates as novel HBV entry inhibitors targeting NTCP receptor.

Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.

Dual site reactivity of indole-3-Schiff bases with S/Se/Cl substituted ketenes for stereoselective C-4 substituted indole-ß-lactams, biological evaluations, magic chloro effect and molecular docking studies.

A convenient methodology for C-4 indole-ß-lactam hybrids with chloro, sulphur and seleno substitutions through dual site reactivity of indole-3-Schiff bases towards ketenes has been developed. The reaction proceeded in a stereospecific manner with the exclusive formation of trans-ß-lactams assigned with respect to C3-H and C4-H. The synthesized novel ß-lactams have been characterized with the help of elemental analysis (CHNS) and spectroscopic techniques viz.1H NMR, 13C NMR, DEPT 135, HSQC and IR. The trans configuration was further estabilished based on X-ray crystallographic data. Examination of antibacterial properties unveiled that only derivatives 5a and 5b, featuring chloro substitution, exhibited potent activities, underscoring the emergence of the recently coined term "magic chloro effect". Molecular docking analysis provided additional support for the observed in vitro antibacterial activities of compounds 5a-b.

Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson's disease.

Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.

Stilbene-pyridazinone hybrids: design, synthesis and in vitro antiplatelet activity screening.

A series of stilbene analogues, in which a phenyl ring was replaced by the pyridazin-3(2H)-one nucleus, was designed and synthesized to be explored as platelet aggregation inhibitors. The proposed stilbene-pyridazinone hybrids were successfully obtained from simple starting materials and by Wittig's reaction. Most of the target compounds displayed improved in vitro activity in comparison with the standard drug, resveratrol, highlighting as the most potent the analogues 10d and 10e, with inhibition percentages of 94.15 % at 100 µM and 100 % at 50 µM, respectively. The pharmacokinetic and toxicity (ADME/T) properties of the novel hybrids were also estimated with the SwissADME and ProTox-II web servers.

Tubulin inhibitors. Selected scaffolds and main trends in the design of novel anticancer and antiparasitic agents.

Design of tubulin inhibitors as anticancer drugs dynamically developed over the past 20 years. The modern arsenal of potential tubulin-targeting anticancer agents is represented by small molecules, monoclonal antibodies, and antibody-drug conjugates. Moreover, targeting tubulin has been a successful strategy in the development of antiparasitic drugs. In the present review, an overall picture of the research and development of potential tubulin-targeting agents using small molecules between 2018 and 2023 is provided. The data about some most often used and prospective chemotypes of small molecules (privileged heterocycles, moieties of natural molecules) and synthetic methodologies (analogue-based, fragment-based drug design, molecular hybridization) applied for the design of novel agents with an impact on the tubulin system are summarized. The design and prospects of multi-target agents with an impact on the tubulin system were also highlighted. Reported in the review data contribute to the "structure-activity" profile of tubulin-targeting small molecules as anticancer and antiparasitic agents and will be useful for the application by medicinal chemists in further exploration, design, improvement, and optimization of this class of molecules.

A survey of isatin hybrids and their biological properties.

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitates the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Molecular hybridization has been established as an efficient technique in designing bioactive molecules capable of fighting infections. Isatin, a core nucleus of an array of compounds with diverse biological properties can be modified at different positions leading to the creation of novel drug targets, is an active area of medicinal chemistry. This review containing published articles from 2005 to 2022 highlights isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The enriched structure-activity relationship studies discussed provides insights for the rational design of novel isatin hybrids with tailored biological properties as effective therapeutic candidates inspired by nature.

Dehydroacetic acid a privileged medicinal scaffold: A concise review.

From the last decade, research on dehydroacetic acid (DHA) and its derivatives has increased immensely due to its significant role in various fields, including medicine, cosmetics, food industry, and so on. In the medicinal area, DHA plays an essential role in developing novel action-based drugs, which are helpful for treating various diseases. Besides its plethora of biological applications, its chelating ability offers the easiest synthetic route for synthesizing more active metal complexes. DHA derivatives along with their metal complexes show a number of biological activities and also exhibit various interactions with multiple biological targets. This article summarizes recent medicinal applications (2000-onwards) of DHA-based compounds and their analogs, along with their structure-activity relationship (SAR) analysis. Their interactions with different target enzymes are also discussed. This information derived from SAR analysis would be helpful for medicinal chemists working on the development of drugs based on heterocyclic frameworks, particularly those based on the DHA scaffold.

Pills of Multi-Target H2S Donating Molecules for Complex Diseases.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, such as inflammatory-based diseases and cancer, as well as cardiovascular, metabolic, and neurodegenerative disorders.

Recent Trends in the Synthesis and Bioactivity of Coumarin, Coumarin-Chalcone, and Coumarin-Triazole Molecular Hybrids.

Molecular hybridization represents a new approach in drug discovery in which specific chromophores are strategically combined to create novel drugs with enhanced therapeutic effects. This innovative strategy leverages the strengths of individual chromophores to address complex biological challenges, synergize beneficial properties, optimize pharmacokinetics, and overcome limitations associated with single-agent therapies. Coumarins are documented to possess several bioactivities and have therefore been targeted for combination with other active moieties to create molecular hybrids. This review summarizes recent (2013-2023) trends in the synthesis of coumarins, as well as coumarin-chalcone and coumarin-triazole molecular hybrids. To cover the wide aspects of this area, we have included differently substituted coumarins, chalcones, 1,2,3- and 1,2,4-triazoles in this review and considered the point of fusion/attachment with coumarin to show the diversity of these hybrids. The reported syntheses mainly relied on well-established chemistry without the need for strict reaction conditions and usually produced high yields. Additionally, we discussed the bioactivities of the reported compounds, including antioxidative, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities and commented on their IC50 where possible. Promising bioactivity results have been obtained so far. It is noted that mechanistic studies are infrequently found in the published work, which was also mentioned in this review to give the reader a better understanding. This review aims to provide valuable information to enable further developments in this field.

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system.

A straightforward protocol for the synthesis of a previously unknown [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-one heterocyclic system was developed. The described approach is based on tandem diazotization/azo coupling reactions of (1,2,5-oxadiazolyl)carboxamide derivatives bearing both aromatic and aliphatic substituents. The NO-donor ability of the synthesized furoxano[3,4-d][1,2,3]triazin-7(6H)-ones was additionally evaluated. The elaborated method provides access to novel nitrogen heterocyclic compounds with potential applications as drug candidates or thermostable components of functional organic materials.

Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

Small molecule tractable PARP inhibitors: Scaffold construction approaches, mechanistic insights and structure activity relationship.

Diverse drug design strategies viz. molecular hybridization, substituent installation, scaffold hopping, isosteric replacement, high-throughput screening, induction and separation of chirality, structure modifications of phytoconstituents and use of structural templates have been exhaustively leveraged in the last decade to load the chemical toolbox of PARP inhibitors. Resultantly, numerous promising scaffolds have been pinpointed that in turn have led to the resuscitation of the credence to PARP inhibitors as cancer therapeutics. This review briefly presents the physiological functions of PARPs, the pharmacokinetics, and pharmacodynamics, and the interaction profiles of FDA-approved PARP inhibitors. Comprehensively covered is the section on the drug design strategies employed by drug discovery enthusiasts for furnishing PARP inhibitors. The impact of structural variations in the template of designed scaffolds on enzymatic and cellular activity (structure-activity relationship studies) has been discussed. The insights gained through the biological evaluation such as profiling of physicochemical properties andin vitroADME properties, PK assessments, and high-dose pharmacology are covered.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis.

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Chromone Containing Hybrid Analogs: Synthesis and Applications in Medicinal Chemistry.

The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogs. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogs. The current review summarizes the rationale and techniques involved in developing hybrid analogs of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogs or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogs have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogs in the field of drug discovery. The importance of hybrid analogs in various disease conditions is also illustrated.

Molecular Hybridization of Alkaloids Using 1,2,3-Triazole-Based Click Chemistry.

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules.