Catalytic role in Biginelli reaction: Synthesis and biological property studies of 2-oxo/thioxo-1,2,3,4-tetrahydropyrimidines.

The Biginelli reaction has received significant consideration in recent years due to its easily accessible aldehyde, urea/thiourea, and active methylene compounds. When it comes to pharmacological applications, the Biginelli reaction end-products, the 2-oxo-1,2,3,4-tetrahydropyrimidines, are vital in pharmacological applications. Due to the ease of carrying out the Biginelli reaction, it offers a number of exciting prospects in various fields. Catalysts, however, play an essential role in Biginelli's reaction. In the absence of a catalyst, it is difficult to form products with a good yield. Many catalysts have been used in search of efficientmethodologies, including biocatalysts, Brønsted/Lewis acids, heterogeneous catalysts, organocatalysts, and so on. Nanocatalysts are currently being applied in the Biginelli reaction to improve the environmental profile as well as speed up the reaction process. This review describes the catalytic role in the Biginelli reaction and pharmacological application of 2-oxo/thioxo-1,2,3,4-tetrahydropyrimidines. This study provides information that will facilitate the development of newer catalytic methods for the Biginelli reaction, by academics as well as industrialists. It also offers a broad scope for drug design strategies, which may enable the development of novel and highly effective bioactive molecules.

Design, synthesis, molecular docking, and biological evaluation of coumarin-thymidine analogs as potent anti-TB agents.

With the intent to discover new antituberculosis (TB) compounds, coumarin-thymidine analogs were synthesized using second-order nucleophilic substitution reactions of bromomethyl coumarin with thymidine. The newly synthesized coumarin-thymidine conjugates (1a-l) were characterized using IR, NMR, GC-MS, and CHN elemental analysis. The novel conjugates were found to exhibit potent anti-TB activity against the Mycobacterium tuberculosis H37 Rv strain, with minimum inhibitory concentrations (MIC) of the active compounds ranging between 0.012 and 0.482 µM. Compound 1k was established as the most active candidate with a MIC of 0.012 µM. The toxicity study on HEK cells confirmed the nontoxic nature of compounds 1e, 1h, 1i, 1j, and 1k. Also, the most active compounds (1k, 1j, and 1e) were stable in the pH range from 2.5 to 10, indicating compatibility with the biophysical environment. Based on the pKa studies, compounds 1k, 1j, and 1e are capable of crossing lipid-membrane barriers and acting on target cells. Molecular docking studies on the M. tuberculosis ß-oxidation trifunctional enzyme (PDB ID: 7O4V) were conducted to investigate the mechanisms of anti-TB activity. All compounds showed excellent hydrogen binding interactions and exceptional docking scores against M. tuberculosis, which was in accordance with the results. Compounds 1a-l possessed excellent affinity to proteins, with binding energies ranging from -7.4 to -8.7 kcal/mol.

Dual functions: A coumarin-chalcone conjugate inhibits cyclic-di-GMP and quorum-sensing signaling to reduce biofilm formation and virulence of pathogens.

Antibiotic resistance or tolerance of pathogens is one of the most serious global public health threats. Bacteria in biofilms show extreme tolerance to almost all antibiotic classes. Thus, use of antibiofilm drugs without bacterial-killing effects is one of the strategies to combat antibiotic tolerance. In this study, we discovered a coumarin-chalcone conjugate C9, which can inhibit the biofilm formation of three common pathogens that cause nosocomial infections, namely, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli, with the best antibiofilm activity against P. aeruginosa. Further investigations indicate that C9 decreases the synthesis of the key biofilm matrix exopolysaccharide Psl and bacterial second messenger cyclic-di-GMP. Meanwhile, C9 can interfere with the regulation of the quorum sensing (QS) system to reduce the virulence of P. aeruginosa. C9 treatment enhances the sensitivity of biofilm to several antibiotics and reduces the survival rate of P. aeruginosa under starvation or oxidative stress conditions, indicating its excellent potential for use as an antibiofilm-forming and anti-QS drug.

ON donor tethered copper (II) and vanadium (V) complexes as efficacious anti-TB and anti-fungal agents with spectroscopic approached HSA interactions.

Antimicrobial drug resistance poses a significant threat worldwide, hence triggering an urgent situation for developing feasible drugs. 3D-transition metal coordination complexes being multifaceted, offer tremendous potency as drug candidates. However, there are fewer reports on non-toxic and safe transition metal complexes; therefore, we hereby attempted to develop novel copper and vanadium-based therapeutic agents. We have synthesised six metal complexes viz., [VVO2(Quibal-INH)] (1), [CuII(Quibal-INH)2] (2), [VVO(Quibal-INH) (cat)] (3), [CuII(Quibal-INH) (cat)] (4), [VVO(Quibal-INH) (bha)] (5) and [CuII(Quibal-INH) (bha)] (6). Quibal-INH (L) is an ON bidentate donor ligand synthesized from Schiff base reaction between 4-(2-(7-chloroquinolin-3-yl)vinyl)benzaldehyde (Quibal) and Isoniazid (INH). The synthesized compounds were characterized using analytical techniques involving ATR-IR, UV-Vis, EPR, 1H NMR, 13C NMR, and 51V NMR. Ligand (L) and compound 3 exhibited moderate growth inhibitory activity towards Candida albicans and Cryptococcus neoformans fungal species. Compound 6 has been identified as active against the above fungal species with no toxicity and hemolysis activity on the healthy cells. Compound 5 exhibited significant activity against the Mycobacterium tuberculosis H 37 R v strain. Further, compounds 4, 5 and 6 exhibited excellent free radical scavenging activity. All the developed compounds were found to exhibit stability over a wide range of pH conditions. The complexes were additionally studied for their interaction with human serum albumin (HSA) with the UV-vis spectroscopic technique.

Drug re-engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery.

The prevalence of tuberculosis (TB) remains the leading cause of death from a single infectious agent, ranking it above all other contagious diseases. The problem to tackle this disease seems to become even worse due to the outbreak of SARS-CoV-2. Further, the complications related to drug-resistant TB, prolonged treatment regimens, and synergy between TB and HIV are significant drawbacks. There are several drugs to treat TB, but there is still no rapid and accurate treatment available. Intensive research is, therefore, necessary to discover newer molecular analogs that can probably eliminate this disease within a short span. An increase in efficacy can be achieved through re-engineering old TB-drug families and repurposing known drugs. These two approaches have led to the production of newer classes of compounds with novel mechanisms to treat multidrug-resistant strains. With respect to this context, we discuss structural aspects of developing new anti-TB drugs as well as examine advances in TB drug discovery. It was found that the fluoroquinolone, oxazolidinone, and nitroimidazole classes of compounds have greater potential to be further explored for TB drug development. Most of the TB drug candidates in the clinical phase are modified versions of these classes of compounds. Therefore, here we anticipate that modification or repurposing of these classes of compounds has a higher probability to reach the clinical phase of drug development. The information provided will pave the way for researchers to design and identify newer molecular analogs for TB drug development and also broaden the scope of exploring future-generation potent, yet safer anti-TB drugs.

Coumarin hybrid derivatives as promising leads to treat tuberculosis: Recent developments and critical aspects of structural design to exhibit anti-tubercular activity.

Tuberculosis (TB) is a highly contagious airborne disease with nearly 25% of the world's population infected with it. Challenges such as multi drug resistant TB (MDR-TB), extensive drug resistant TB (XDR-TB) and in rare cases totally drug resistant TB (TDR-TB) emphasizes the critical and urgent need in developing novel TB drugs. Moreover, the prolonged and multi drug treatment regime suffers a major drawback due to high toxicity and vulnerability in TB patients. This calls for intensified research efforts in identifying novel molecular scaffolds which can combat these issues with minimal side effects. In this pursuit, researchers have screened many bio-active molecules among which coumarin have been identified as promising candidates for TB drug discovery and development. Coumarins are naturally occurring compounds known for their low toxicity and varied biological activity. The biological spectrum of coumarin has intrigued medicinal researchers to investigate coumarin scaffolds for their relevance as anti-TB drugs. In this review we focus on the recent developments of coumarin and its critical aspects of structural design required to exhibit anti-tubercular (anti-TB) activity. The information provided will help medicinal chemists to design and identify newer molecular analogs for TB treatment and also broadens the scope of exploring future generation potent yet safer coumarin based anti-TB agents.

Biscoumarin-pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin.

In our continuing efforts to develop therapeutically active coumarin-based compounds, a series of new C4-C4' biscoumarin-pyrimidine conjugates (1a-l) was synthesized via SN 2 reaction of substituted 4-bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR-IR), CHN elemental analysis, and 1 H and 13 C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3-bis[(7-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione) was established through X-ray crystallography. Compounds 1a-l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3-bis[(6-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (1c) was identified as the best antiproliferative candidate, exhibiting an IC50 value of 4.85 µM. All the compounds (1a-l) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound (1c) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV-visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein.

Physicochemical, in-vitro therapeutic activity and biomolecular interaction studies of Mn(II), Ni(II) and Cu(II) complexes tethered with O2N2 ligand backbone.

Two major health crisis of today's world are antimicrobial drug resistance and type II diabetes. To tackle them, there is an immediate requirement for the development of new and safer drugs and the present work is one such quest for novel and efficient drug candidates. We have developed three trace metal coordination compounds tethered with a reduced salen ligand {H2(hpdbal)2-an} (L), namely, a manganese-salan complex, [MnII(H2O)2{(hpdbal)2-an}] (1), a nickel-salan complex, [NiII{(hpdbal)2-an}] (2) and a copper-salan complex, [CuII{(hpdbal)2-an}] (3). The compounds were characterized by elemental analysis, vibrational spectroscopy, electronic spectroscopy, thermogravimetric analysis, nuclear magnetic resonance and electron-paramagnetic resonance techniques. The compounds were evaluated for antimicrobial activity against seven pathogens (Escherichia coli, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Cryptococcus neoformans) and antidiabetic activity by mimicking diabetic environment on the immortal human liver cancer cells, HepG2. Complexes 1 and 2 were additionally tested for their reactivity and stability in biological media mimic conditions. The nickel(II) salan complex (2) exhibited noteworthy antifungal activity against Candida albicans and the manganese(II) salan complex (1) induced increased glucose uptake by the insulin resistant cells. Both compounds were found to be stable when solution pH conditions were varied from 3 to 9. They exhibited strong affinity of binding towards a carrier protein, bovine serum albumin which was evaluated with the aid of multi-spectroscopic techniques.

A manganese (II) complex tethered with S-benzyldithiocarbazate Schiff base: Synthesis, characterization, in-vitro therapeutic activity and protein interaction studies.

There is an urgent need to eliminate the era of superbugs through design and development of novel and sustainable drugs. Transition metal complexes can be one of the hopes for tackling drug resistant pathogens. In this view, we have developed a manganese complex appended with an ON donor ligand which has shown excellent activity against one of the prominent fungal species. The Mn (II) complex, [MnII(OH2)2(Hhpdbal-sbdt)2] (1) was synthesized using a Schiff base ligand derived from an azo aldehyde and S-benzyldithiocarbazate. The complex was characterized with the help of analytical techniques such as elemental analysis, FT-IR, EDAX, EPR and TGA. The solution behavior in physiological conditions and in biological media was preliminarily evaluated by studying the behavior of complex in varied pH conditions and in the presence of protein, BSA. The effect of the compound on few drug resistant pathogenic species of bacteria and fungi and on the uptake of glucose by insulin resistant cells was evaluated using whole cell inhibition assay and NBDG assay respectively. The study gave a noteworthy result with respect to the manganese compound's biological activity, with an inhibitory activity of 93% towards a fungi species, Cryptococcus neoformans and with a relatively good glucose uptake inducing capacity. The manganese complex, which maintains its stability over a wide range of pH conditions and interacts with serum protein, BSA in a facile manner can be an excellent drug candidate and eventually be added to the library of compounds being screened for in vivo activity studies.

Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin.

A series of novel coumarin-cyclic imide conjugates (1a-1j) were designed and synthesized to evaluate their glucose uptake activity by insulin resistant liver hepatocyte carcinoma (HepG2) cells through 2-NBDG uptake assay. Compounds (1a-1j) were characterised using various analytical methods such as 1H NMR, 13C NMR, IR, GC-MS, elemental and single-crystal X-ray diffraction techniques. Compounds (1a-1j) exhibited 85.21 - 65.80% of glucose uptake and showed low level of cytotoxicity towards human embryonic kidney cells (HEK-293) indicating good selectivity and safety profile. Compound 1f was identified as a hit candidate exhibiting 85.21% of glucose uptake which was comparable with standard antidiabetic drug Metformin (93.25% glucose uptake). Solution stability study under physiological pH conditions ≈ (3.4 - 8.7), indicates that compound 1f is sufficiently stable at varied pH conditions and thereby compatible with bio-physiological environments. Interaction of 1f with human serum albumin (HSA) were also studied which quantifies that compound 1f binds with HSA efficiently through facile binding reaction in solution. Fluorescence, UV-vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1f with protein.

In vitro apoptosis-induction, antiproliferative and BSA binding studies of a oxidovanadium(V) complex.

In our ongoing efforts to develop novel trace metal complexes with therapeutically interesting properties, a neutral mono nuclear oxidomethoxidovanadium(V) complex, [VVO(OCH3)(hpdbal-sbdt)] (1) and a µ-O bridged dinuclear oxidovanadium(V) complex, [{VVO(hpdbal-sbdt)}2µ-O] (2) [H2hpdbal-sbdt (I) is a tridentate and dibasic ONS2- donor ligand obtained through the Schiff base reaction of 2-hydroxy-5-(phenyldiazenyl)benzaldehyde (Hhpdbal) and S-benzyldithiocarbazate (Hsbdt)] have been synthesized and characterized by various analytical techniques such as TGA, EDS, ATR-IR, UV-Vis, CV, 1H NMR, 13C NMR and 51V NMR. Single-crystal X-ray diffraction analysis of 1 confirms the coordination of phenolate oxygen, imine nitrogen and thioenolate sulfur of the ligand to the vanadium center with a distorted tetragonal-pyramidal geometry. The compound 2 triggered apoptotic and reproductive death of the cancer cells in vitro with 76% and 62% growth inhibition of human breast adenocarcinoma (MCF-7) and human lung carcinoma cells (A549) respectively. The compound 2 was found to be sufficiently stable over a wide window of physiological pH. The complex 2 was studied further for its interaction with a drug carrier protein BSA with the aid of spectroscopic techniques viz. fluorescence, temperature controlled UV-vis and deconvoluted IR techniques.

A novel biocompatible NiII tethered moiety as a glucose uptake agent and a hit against methicillin-resistant Staphylococcus aureus.

In the efforts to develop a biocompatible transition metal complex as a drug alike for some of the prevailing non-communicable diseases (NCDs) and communicable diseases (CDs), a novel binuclear NiII compound [{NiII(hpdbal-sbdt)}2] (2) has been synthesized by the reaction of Ni(OAc)2.4H2O and H2hpdbal-sbdt (1) [1 is a dibasic tridentate ONS2- donor Schiff base ligand obtained by the condensation of 2-hydroxy-5-(phenyldiazenyl)benzaldehyde (Hhpdbal) and S-benzyldithiocarbazate (Hsbdt)]. Both ligand 1 and compound 2 were structurally characterized in the solid and solution state using various spectroscopic techniques like ATIR, 1H NMR, 13C NMR, TGA, FESEM, EDS and CHNS analysis. The antidiabetic activity of H2hpdbal-sbdt (1) and [{NiII(hpdbal-sbdt)}2] (2) were assessed using 2-NBDG uptake assay. The assay results showed 85% and 95% of fluorescent glucose uptake by insulin resistant HePG2 cells treated with compounds 1 and 2 respectively. The 2-NBDG uptake by the cells treated with the compound 2 was observed to be comparable to the standard antidiabetic drug metformin. Compounds 1 and 2 were also tested against five bacterial and two fungi strains in order to evaluate pathogen killing activity. Compound 2 showed significant inhibitory action towards the methicillin-resistant Staphylococcus aureus (MRSA) strain with an MIC value of 2 µg/mL whereas the ligand 1 was found to be inactive. Furthermore, the interactive nature of compound 2 with a model serum carrier protein bovine serum albumin (BSA) was studied using a multi-spectroscopic approach which provided an insight into the nature and extent of binding, conformational changes and the quenching of amino acid residues of the protein.

Synthesis and evaluation of novel coumarin-oxime ethers as potential anti-tubercular agents: Their DNA cleavage ability and BSA interaction study.

As a contribution to the development of novel coumarin-oxime ether conjugates with therapeutically interesting properties, a series of coumarin-oxime ether (1a-1j) was synthesised using SN2 reaction of bromomethyl coumarins with butane-2,3-dione monoxime. Invitro anti-tuberculosis activityagainstMTBH37Rv strain was established for the coumarin-oxime ether (1a-1j). Most of the compounds exhibited significant activity with minimum inhibitory concentration (MIC)in the range of 0.04-3.12 µg mL-1. Compound (1h) was identified as a hit candidate exhibiting MIC of 0.04 µg mL-1, closer to the MIC value of Isoniazid (0.02 µg mL-1), a commercially available drug for the treatment of tuberculosis. Compound 1h also displayed a low level of toxicity in Vero cells along with a good safety profile in vitro. Compounds that showed potent anti-tubercular activity were also found to cleave DNA more efficiently and thereby exhibit nuclease activity. The most active compound (1h) was further studied to deduce the mode of interaction with model serum protein, bovine serum albumin (BSA).

Design, synthesis of benzocoumarin-pyrimidine hybrids as novel class of antitubercular agents, their DNA cleavage and X-ray studies.

A series of 2-(2-(4-fluorobenzyl)-6-(substituted phenyl) pyrimidin-4-yl)-3H-benzo[f]chromen-3-one derivatives (1a-1o) were selectively prepared in high yields under microwave irradiation. The synthesized compounds were characterized by elemental and spectroscopic analysis; in addition the structures of compound (1a), (1b) and (1j) were elucidated by the X-ray diffraction technique. Compounds (1a-1o) were evaluated for their in-vitro antitubercular activity while the most active compounds were further subjected for their cytotoxicity and DNA cleavage study. Results revealed that most of the tested compounds displayed potent antitubercular activity with MIC in the range 0.05-2.81 µg/mL. Among them, compound (1b) possessed excellent activity (MIC 0.05 µg/mL) against M.tb H37Rv strain and exhibited low level of cytotoxicity against Vero cells, which suggested compound (1b) is a promising lead for subsequent investigation in search of new antitubercular agents. DNA cleavage by gel electrophoresis method revealed that compounds (1b, 1g, 1k and 1n) were found to cleave the DNA completely.