The obstinatproblem of drug resistance in tuberculosis (TB) requires sustained efforts in the search for new drug molecules. Building on our previously developed synthetic hybrid compound, UH-NIP-16, which demonstrated anti- (M.tb) activity, we synthesized and evaluated 15 new derivatives to improve its potency. Among these, two lead compounds, UN-7 and UN-14, bearing hydrogen and methyl substitutions at the sixth position, respectively, along with a 2-phenoxy moiety, exhibited a similar to 5-fold reduction in MIC50 values across laboratory, clinical, and multidrug-resistant M.tb strains relative to UH-NIP-16. Both compounds displayed a bacteriostatic mechanism of action and exhibited predominantly additive or indifferent interaction profiles in combinatorial antitubercular studies. Importantly, UN-7 and UN-14 showed minimal cytotoxicity toward mammalian cells and effectively reduced intracellular bacterial burden in an in vitro infection model. A coupled enzymatic assay revealed that UN-7 and UN-14 inhibited mycobacterial shikimate kinase (Mt-SK) activity by approximately 65%, a target not inhibited by the parent compound UH-NIP-16. In silico ADMET analyses indicated several favorable drug-likeness properties despite predicted liabilities, including Ames mutagenicity and low aqueous solubility. Collectively, these findings identify UN-7 and UN-14 as structure-activity relationship (SAR)-guided derivatives of the UH-NIP-16 scaffold with improved antimycobacterial activity and promising potential for further antitubercular lead development.

In the present study, we have developed a Baker’s yeast (BY) mediated efficient and mild nitration of aromatic compounds. The results of nitration clearly showed that it is a highly regio-selective method, when aromatic compounds (1a–1h) were nitrated by using the BY/nitric acid system and gave corresponding nitro derivatives (2a–2h) in good to excellent yield. The present reaction condition is advantageous as it follows a normal procedure and requires a simple workup, adhering to green chemistry principles. Thus, we can conclude that the present nitration method is a simple, efficient, regio-selective, and eco-friendly method under bio-catalysis conditions.

The obstinatproblem of drug resistance in tuberculosis (TB) requires sustained efforts in the search for new drug molecules. Building on our previously developed synthetic hybrid compound, UH-NIP-16, which demonstrated anti-Mycobacterium tuberculosis (M.tb) activity, we synthesized and evaluated 15 new derivatives to improve its potency. Among these, two lead compounds, UN-7 and UN-14, bearing hydrogen and methyl substitutions at the sixth position, respectively, along with a 2-phenoxy moiety, exhibited a ∼5-fold reduction in MIC50 values across laboratory, clinical, and multidrug-resistant M.tb strains relative to UH-NIP-16. Both compounds displayed a bacteriostatic mechanism of action and exhibited predominantly additive or indifferent interaction profiles in combinatorial antitubercular studies. Importantly, UN-7 and UN-14 showed minimal cytotoxicity toward mammalian cells and effectively reduced intracellular bacterial burden in an in vitro infection model. A coupled enzymatic assay revealed that UN-7 and UN-14 inhibited mycobacterial shikimate kinase (Mt-SK) activity by approximately 65%, a target not inhibited by the parent compound UH-NIP-16. In silico ADMET analyses indicated several favorable drug-likeness properties despite predicted liabilities, including Ames mutagenicity and low aqueous solubility. Collectively, these findings identify UN-7 and UN-14 as structure-activity relationship (SAR)-guided derivatives of the UH-NIP-16 scaffold with improved antimycobacterial activity and promising potential for further antitubercular lead development.

ABSTRACT Coumarin chemically is a 2 H ‐1‐benzopyran‐2‐one and belongs to the lactone family. Coumarins and its derivatives is important scaffold which is present in most of natural products and synthetic compounds. The conjugated double ring system makes these molecules useful for the different fields of research. The versatile scaffold of coumarin is playing vital role in the medicinal field. The derivatives of coumarin exhibit broad range of biological application which includes antimicrobial, antiviral, anti‐HIV activity, anti‐inflammatory, antioxidant, anticancer and antifungal. In recent years, a huge number of coumarin derivatives have been designed, synthesized, and tested for their activity for several therapeutically diseases. In many instances, these properties have been enhanced by incorporating suitable pharmacophores. In this review we present the synthesis of coumarins derivatives which are synthesized via Pechmann reaction under various reaction conditions and their biological applications for the therapeutic applications.

Background8-Hydroxyquinoline and 4-thiazolidinone derivatives are promising antimicrobial agents, recognized for their activity against resistant pathogens.AimThe aim of this study is to develop 8-hydroxyquinoline-4-thiazolidinone derivatives as potential antimicrobial agents.MethodsUsing a one-pot reaction with sodium tetrafluoroborate as an efficient and eco-friendly catalyst, compounds 6a - l were synthesized and subsequently screened for antibacterial and antifungal activity. Additionally, molecular docking and molecular dynamic simulations were performed to evaluate the active compounds and gain deeper insights into their potential as antimicrobial agents.ResultsCompounds 6f and 6 g showed superior antibacterial activity to ciprofloxacin, particularly against Gram-negative bacteria, while 6b, 6 g, and 6 h demonstrated strong antifungal effects. Molecular docking, molecular dynamics simulations, and MM-GBSA calculations highlighted strong binding interactions and stable conformations of the active compounds within binding pocket of the FabZ enzyme. The ADMET analyses further indicated that these compounds possess favorable drug-like properties.ConclusionThe synthesized 8-hydroxyquinoline-4-thiazolidinone hybrids exhibit strong potential as broad-spectrum antimicrobial agents and merit further investigation as drug candidates.

Carbonic anhydrase inhibitors (CAIs) have garnered significant attention in recent years due to their critical role in managing various diseases, including glaucoma, epilepsy, cancer, and other conditions linked to carbonic anhydrase (CA) isoforms. This review highlights the recent advancements in the design and development of CAIs, focusing on diverse chemical classes such as indoles, sulfocoumarins, 1,2,3-triazoles, urea derivatives, chalcones, quinolines, and pyridines. Each class presents unique structural features and mechanisms of action, contributing to the selective inhibition of specific CA isoforms. The ongoing exploration of these compounds has not only enhanced our understanding of CA inhibition but also opened new avenues for therapeutic applications, paving the way for the development of novel drugs that tackle pressing healthcare challenges.

In the present study a series new 8-hydroxyquinoline-Benzimidazole hybrids (6a–l) were designed, synthesized (6a–l) by using conventional synthetic methods and assayed for their antimicrobial evaluation. The newly synthesized compounds (6a–l) were screened for their antibacterial activity against four strains i.e., E. coli, S. aureus, P. aeruginosa and B. subtilis and antifungal activity tested against A. niger and C. albicans. The compounds 6b, 6c, 6g, 6h, 6i, 6k and 6l are found to be active against all 4 bacterial strains. The compounds 6a, 6b, 6c, 6g, 6h, 6i, 6k and 6l are showing almost same antifungal activity when compared to the standard drug Voriconazole against A. niger. Whereas, In the case of C. albicans the compounds 6c, 6g, 6h, 6i, 6j, 6k and 6l are showing good antifungal activity. The MIC studies revealed that these compounds were showing the MIC values between 3.9 and 62.5 μg/ml for all the four bacterial strains. Among all the compounds, the compound 6g was showing the 3.9 μg/ml MIC value for E. coli and P. aeruginosa and found to be most potent compound antibacterial agent. From the results of the MIC studies exhibit that these compounds were good antifungal agents and showing the MIC values ranging between 19.2 and 500 μg/ml for both A. niger and C. albicans. The compound 6f was emerged as most potent antifungal agent by exhibiting the 22.3 μg/ml MIC value for A. niger and 19.2 μg/ml MIC value for C. albicans. Thus it is anticipated that these compounds will emerged as potential antibacterial as well antifungal agents on further exploration.

An efficient and facile method has been developed for the synthesis of 3-indolylmethanamine via the Aza-Friedel Crafts Reaction of indole with imines by using Baker’s Yeast as biocatalyst. The reaction is very facile and works under mild and eco-friendly environment condition as ethyl alcohol (C2H5OH) is used as green solvent and Baker's Yeast as biocatalyst. Furthermore, the present method is very efficient as it requires simple work up and gives the products in good to excellent yields. It is anticipated that the present newly developed method will open a new route for the chemists to prepare the 3-indolylmethanamine via the Aza-Friedel Crafts Reaction of indole with imines in facile and eco-friendly environment.

Treating hypoxic tumors is challenging due to their aggressive nature, resistance to standard treatments, often leading to poor outcomes. Hypoxic tumors create a unique environment that reduces the effectiveness of traditional treatments such as chemotherapy and radiotherapy. Human carbonic anhydrases (hCA IX and hCA XII) are involved in tumors survival and metabolism by regulating pH homeostasis, ferroptosis, metastatization, and other processes. Developing drugs that specifically target these enzymes has been demonstrated to disrupt the tumor survival mechanisms, leading to significant antitumor effects. This review discusses recent developments on antibody-drug conjugates (ADCs) and radioconjugates targeting hCA IX and hCA XII in hypoxic tumors. New approaches based on small molecule inhibitors and monoclonal antibodies such as girentuximab provided encouraging results in preclinical research and clinical trials. These advances highlight the potential of hCA-targeted therapies to improve cancer treatment for hypoxic tumors.

M1 aminopeptidase is a metallopeptidase that plays a vital role in protein catabolism and has been identified as a validated drug target in various parasites; however, our understanding of this enzyme is restricted for leishmanial parasite. The present investigation involved the purification of Leishmania donovani M1 aminopeptidase (LdM1AP) to homogeneity by affinity chromatography. Purified LdM1AP was observed to be enzymatically active and displayed maximal activity in the presence of cobalt ions, whereas secondary structure analysis confirmed the dominance of α-helices. Intrinsic fluorescence and quenching studies of LdM1AP has revealed that tryptophan residues were predominantly concealed within the hydrophobic areas. The synthesized quinoline-carbaldehyde derivatives were screened, wherein HQ2 and HQ12 were found as potent inhibitors for LdM1AP that compete with the substrate and exhibit pharmacokinetic properties as well as no toxicity for macrophages. Moreover, structural insights of protein and ligand complexes demonstrated that lead compounds mostly interact via hydrophobic contacts into the substrate binding pocket of LdM1AP. Furthermore, lead compounds exhibited a greater affinity for LdM1AP compared to the substrate during in vitro and in silico studies. This report establishes the possibility of quinoline derivatives to target the LdM1AP activity and provide a platform to design the specific antileishmanial drugs.

BACKGROUND:Sulfonamide derivatives are well-reported hCA IX inhibitors; however, they inhibit all types of hCA without any selectivity, leading to severe adverse effects. Hence, developing a novel nonsulfonamide class of tumor-associated hCA IX inhibitors through non-classical inhibition may provide greater selectivity and better pharmacokinetics. OBJECTIVE:The objective of this study was to develop non-sulfonamide derivatives as potential human carbonic anhydrase (hCA) inhibitors and develop a new series of chromene-linked bis-indole derivatives. METHODS:We synthesized and characterized the chromene-linked bis-indole derivatives and further evaluated them against four hCA isoforms, i.e., hCA I, hCA II, hCA IX, and hCA XII, and determined the ADMET parameters by the In-silico method. RESULTS:Most of the compounds showed significantly greater affinity and selectivity towards the tumorassociated hCA IX over other hCA isoforms within the lower micromolar to submicromolar range. In particular, the bromo-substituted bis-indole derivative 6t showed an excellent inhibition of hCA IX isoform with an affinity (Ki) of 2.61 μM. In contrast, the cyano group substituted bis-indole derivative 6s and also displayed a strong inhibition of hCA IX isoform with an affinity (Ki) of 2.73 μM. Many other potential candidates, including 6g, 6i, 6k, 6m, 6o, 6p, and 6r, showed higher affinity at tumor-associated hCA IX with lower than 10 μM compared to other hCA isoforms. CONCLUSION:Therefore, the chromene-linked bis-indole derivatives can serve as a novel non-sulfonamide class of tumor-associated hCA IX inhibitors.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 μM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 μM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.

A green and facile synthesis of 1-(alpha-aminoalkyl)-2-naphthols, generally called Betti bases (BB) in the presence of Baker's yeast (BY), acts as an efficient catalyst, and ethanol as a green solvent. In this methodology, the BY is used first time as a biocatalyst (enzyme). This protocol has some inherent advantages, such as mild reaction conditions, no environmental pollution, simple work up, no need of column chromatography, diversity of reactant and desired 1-(alpha-aminoalkyl)-2-naphthols (Betti bases) (4a-r) are obtained in good-to-excellent yields. This is the first report on Baker's yeast-catalyzed (BYC) synthesis for BB. This present bio-catalytical route for synthesizing BB in the presence of biocatalysts like BY is anticipated to open a gateway to synthesized complexed biological active molecules counting BB.

The coumarin is one of the most promising classes of non-classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In continuation of our ongoing work on search of coumarin based selective carbonic anhydrase inhibitors, a new series of 6-aminocoumarin based 16 novel analogues of coumarin incorporating thiazole (4a-p) have been synthesized and studied for their hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants in the nanomolar range. Among the tested compounds, the compounds 4f having 4-methoxy substitution exhibited activity at 90.9 nM against hCA XII isoform. It is noteworthy to see that all compounds were specifically and selectively active against isoforms hCA IX and hCA XII, with Ki under 1000 nM range. It is anticipated that these newly synthesized coumarin-thiazole hybrids (4a-p) may emerge as potential leads candidates against hCA IX and hCA XII as selective inhibitors compared to hCA I and hCA II.

A new series of isatin-linked benzenesulfonamide derivatives (9a-w) were synthesized using the tail approach and assayed for their inhibitory potency against four different human carbonic anhydrase (hCA) isoforms, hCA I, II, IX, and XII. Most of these synthesized compounds exhibited interesting inhibition potency against isoforms hCA I, IX, and XII in the nanomolar range and by taking the standard drug acetazolamide. The most potent compounds in the case of hCA I were 9c (435.8 nM) and 9s (956.4 nM), for hCA IX, 9a (60.5 nM), 9d (95.6 nM), 9g (92.1 nM), and 9k (75.4 nM), and for hCA XII, 9p (84.5 nM). However, these compounds showed more selectivity toward hCA IX over hCA I, II, and XII. Thus, these compounds can be further developed as potential lead molecules for the development of isoform-selective hCA IX inhibitors with further structural modifications.

The emergence of tumor-associated human carbonic anhydrases (hCA) as promising therapeutic targets has urged rigorous research into the development of potent and selective hCA IX and XII inhibitors. Rationalization of targeting tumor-specific hCA isoforms is a major challenge that requires a comprehensive understanding of the interactions between inhibitors and the dynamic hCA active site. The benzenesulfonamides and its bioisosteres are currently being used clinically as inhibitors of various hCA isoforms through classical inhibitory mechanism. In addition, several other chemotypes have also been developed with improved potency and selectivity through non-classical inhibitory mechanisms. Coumarin and its derivatives represent highly selective and potent inhibitors of hCA IX and XII. Recently, various other pharmacophores were also proven to have a strong selectivity and potency against hCA IX and XII including pyrazole, 1,2,3-triazole, 4-thiazolidinone, and thiourea. This review navigates through understanding the role of hCA IX and XII in cancer biology, encompassing different inhibition approaches, strategic design methodologies, recent advancements in the rational design of hCA inhibitors, exploration of structure-activity relationships, in-depth mechanistic insights, and PET imaging applications for in vivo visualization of target enzymes.

Pyrazoline derivatives exhibit potential application as sensitive and selective chemosensors for the recognition of Fe3+ ions. Their distinctive structure has both donating and accepting sites and is delineated by delocalized orbitals. Through intramolecular charge transfer (ICT), ligand-to-metal charge transfer (LMCT), chelation-enhanced quenching (CHEQ), and H-bond interactions, pyrazoline derivatives show remarkable chromogenic and fluorogenic capabilities. The pyrazoline sensors demonstrated excellent selectivity, low detection limit, and precise metal ion detection. This mini-review provides a guide for utilizing pyrazoline-based "On-Off" chemosensors to identify Fe3+ in diverse fields.

An efficient and reliable method has been developed for chemo-selective synthesis of Schiff bases (SB) (3a-n) by using Baker's yeast (BY) as biocatalyst. The reaction is highly chemo-selective as only benzaldehydes take part in the reaction, whereas acetophenones fail to take part in this reaction. Furthermore, it was observed that amino acids (glycine, phenylalanine & tryptophan) and aliphatic amines (isopropyl amine and 1-amino butane) did not take part in the reaction. The present method is very efficient as it involves simple work up and gives the products in good to excellent yield. The reaction is totally carried out under eco- friendly and environmentally begin conditions by using ethanol (EtOH) as a green solvent. Thus it is anticipated that the present newly developed method will open a gateway for the chemist to prepare the selective SB (Aldimines) in the presence of ketones in facile and eco-friendly conditions.

Background: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Inhibition of isoforms IX and XII has induced potent anticancer effects. Objective: A series of indole-3-sulfonamide-heteroaryl hybrid (6a-y) was synthesized and screened for the inhibition of human (h) hCA isoforms I, II, IX, and XII. Methods: The synthesis of target compounds (6a-y) was carried out in multistep starting from 5-nitro indole as starting material by using classical reported reaction conditions. The steps involved are N-Alkylation Chlorosulfonation, amination, reduction, and finally amidation reaction. Results: Amongst all the compounds (6a-y) synthesized and screened, 6l was found to be active against all the screened hCA isoforms, with Ki ranging 8.03 μM, 4.15 μM, 7.09 μM, and 4.06 μM respectively. On the other hand, 6i, 6j, 6q, 6s, and 6t were highly selective against tumor-associated hCA IX, and 6u was selective against both hCA II and hCA IX with moderate inhibitory activities under the range of 100 μM. These compounds showed good activity against the tumor-associated hCA IX and might be developed as future drug leads for anticancer drug discovery. Conclusion: These compounds may be useful as starting points for the design and development of more selective and potent hCA IX and XII inhibitors.

Evolution of new variants of SARS-CoV-2 warrant the need for the continued efforts in identifying target-oriented new drugs. Dual targeting agents against MPro and PLPro not only overcome the incomplete efficacy but also the drug resistance, which is common problem. Since both these are cysteine proteases, we designed 2-chloroquino-line based molecules with additional imine moiety in the middle as possible nucleophilic warheads. In the first round of design and synthesis, three molecules (C3, C4 and C5) inhibited (Ki < 2 mu M) only MPro by binding covalently to C145 and one molecule (C10) inhibited both the proteases non-covalently (Ki < 2 mu M) with negligible cytotoxicity. Further conversion of the imine in C10 to azetidinone (C11) improved the potency against both the enzymes in the nanomolar range (820 nM against MPro and 350 nM against PLPro) with no cytotoxicity. Conversion of imine to thiazolidinone (C12), reduced the inhibition by 3-5 folds against both the enzymes. Biochemical and computational studies suggest that C10-C12 bind in the substrate binding pocket of MPro and in the BL2 loop of the PLPro. Since these dual inhibitors have least cytotoxicity, they could be further explored as therapeutics against the SARS-CoV-2 and other analogous viruses.