Letters in Drug Design & Discovery - Volume 20, Issue 10, 2023

Enzymes are highly specific catalysts that accelerate reactions in biological systems. Carbonic anhydrase (CA) is an enzyme found in plants, microorganisms, and vertebrates. CA catalyses CO2 hydration/ dehydration. There are different families and isoenzymes of CAs. Fifteen α-CA isoenzymes have been reported in humans. The status of CO2 hydration and dehydration is important for a variety of biological processes. CAs play an important role in many physiological and pathological events in several tissue types. Their levels are increased in some diseases; therefore, CA inhibition has been applied as a therapeutic option. However, the high diversity of these isoenzymes is an important consideration. Isoenzyme- specific CA inhibitors can reduce the side effects of treatment. Some agents containing additional sulfonamides approved for other therapeutic applications, such as topiramate, celecoxib/valdecoxib, sulpiride, and famotidine, have inhibitory effects on CA isoenzymes. These bind to the zinc ion in the CA active site. Recently, research has been conducted on the use of a hybrid form of active ingredient and a CA inhibitor. CA inhibitor-NSAID hybrid compounds demonstrated more efficacy than NSAIDs in arthritis, which has attracted further attention of researchers in conducting research on CA-hybrid drugs.

Metastases result from a complicated process in which malignant cells detach from the initial cancerous cells and disseminate to other locations. Few therapy options are available that aim to prevent or counteract metastatic disorders. Identifying novel molecular targets and medications, developing techniques to distribute preexisting chemicals, and combining resources to supervise individualized treatment are all part of this process. Because of its improved sensitivity, accuracy, and multiplexed measurement capacity, nanotechnology has been investigated to recognize extracellular cancer biomarkers, cancer cells, and bioimaging. Nanotechnology is a vast and rapidly expanding field with enormous potential in cancer treatment. Nanoparticles can treat resistant cancers with minimal harm to healthy tissues and organs by targeting cancer stem cells. Nanoparticles can also trigger immune cells, which can help to destroy malignancies. The potential of herbal-based nano formulation as a specialized and high-efficacy therapeutic method opens the path for future research into the screening and use of herbal nanoparticles for cancer treatment. The possible impacts of nanoparticles in the therapy of metastatic cancer, specifically on cell stability, proliferation suppression, eventual interaction with adhesion molecules, and antiangiogenic activity, are discussed in this paper.

Epilepsy is a chronic neurological disorder characterized by periodic and unpredictable seizures affecting the neurobiological, psychological, cognitive, economic, and social well-being of patients. It is one of the causes of concern in developed as well as developing countries as currently marketed drugs are not capable of providing protection against it. Although several heterocyclic moieties have been frequently used as building blocks for the preparation of anticonvulsant drugs, more focused and consistent research on the synthesis of potential molecules with less adverse effects is the need of the hour. It can be concluded on the basis of available research reports that among several heterocyclic compounds, benzo-fused five-membered heterocyclic moieties (benzothiazole and benzimidazole) have been utilized far less than their great potential as building blocks for the synthesis of anticonvulsant drugs. Various reports clearly established that the required pharmacophore model could be easily achieved through benzothiazole and benzimidazole moieties as two hetero atoms and aryl rings are present in the structure. The present study highlights various synthetic approaches for anticonvulsant benzothiazole and benzimidazole derivatives with their structure-activity relationship studies in order to provide a trove of knowledge to medicinal chemists for future research.

Vitamin K2 products were first applied to Japanese children, which can promote the growth of children's bones and eliminate their growing pain. At the same time, it does little harm to the human body, so it has attracted the attention of some scholars. Later, it was also proved to be effective in treating osteoporosis, especially for postmenopausal women. After years of research, some capabilities of VK2 have been discovered; it has been proved that it has great clinical value in treating osteoporosis, reducing intimal lipid deposition, diabetes, tumor, immune diseases, nervous system diseases and other diseases. There is no doubt that VK2 is an essential nutrient for human health, once vitamin K2 is deficient, it will cause a series of diseases. In recent years, some new evidences show that VK2 can also be used in leukemia and other diseases, which shows that VK2 still has great development potential. As a new adjuvant drug, VK2 has attracted worldwide attention and has been used in the clinic for many years. In this article, we mainly summarized the related research of VK2 in recent years, and expounded on several VK2-related signal pathways and the related mechanisms of these signal pathways in treating various diseases.

The computational method is widely used in the field of drug design as well as discovery. It aids the drug discovery and design process by making the procedure faster while also ensuring fewer human errors. Cancer is a condition with the development of abnormal cells expressing features like uncontrolled growth and cell division. This leads to abnormal tissue enlargement and interrupts the normal functioning of the tissue. Computational methods, mainly the molecular docking method, have been utilised extensively in the field of anticancer drug discovery. Docking is a virtual screening method that can be performed on a large database of compounds. Molecular docking helps in identifying the predominant binding modes of a ligand with a protein whose three-dimensional structure is known. The docking process can predict the method of inhibition of the target molecule by the ligand molecule. Utilities of molecular docking include structure-activity relationship studies, lead identification by virtual screening, optimization of the identified lead, combinatorial library design and more. This review discusses the process of docking, its role in anticancer drug discovery, and a comparison of different docking software. Docking programs are used to make the docking process much more quick, efficient, and with fewer human errors, as it mostly depends on computational algorithms. A description of some representative studies in anticancer drug discovery related to selected docking software, Autodock, SwissDock, ICM, GOLD and Glide, are also mentioned. This paper concludes by emphasizing the importance of docking programs in the field of drug discovery and how it influences the modern drug discovery processes.

Background: Plants have played an essential role in the search for new compounds for the most diverse therapeutic purposes. Recently, more attention has been paid to natural antioxidants because of the possible insecurity of synthetic antioxidants Objective: The review is aimed at summarizing the most important and common natural antioxidants and their resources from medicinal plants. Methods: The research was performed using databases of PubMed, Google Scholar, Science Direct, Taylor and Francis, etc., to search for all collected scientific publications. Results: The most important medicinal plants with antioxidant activities in Iran are Artemisia, berberry fruit, borage, calendula, coriander, cumin, green tea, hawthorn, jujube, pomegranate, rose, rosemary, black zira, tea, and thyme. Important traditional medicinal plants with antioxidant activities in China are Asparagus, bindii, blueberries, camellia, Chinese bayberry, Chinese bitter melon, Chinese cabbage, Chinese cherry, Chinese jujube, Chinese olive, pomegranate, Chinese rose tea, Chinese toon, Chinese watermelon, black tea, knotweed, Chinese quince, Chinese rhubarb, sumac, wolfberry, dendrobium, drumstick tree, Fiscus species, ginger, ginkgo, goji berry, grape, Jerusalem thorn, kiwifruit seed oil, and liquorice root. Anacardium occidentale L., Ananas comosus (L.) Merril, Baccharis trimera (Less) DC., Carapa guianensis Aubl., Casearia sylvestris Sw., Cordia verbenacea DC., Croton lechleri Müll. Arg., and Eugenia uniflora L. are the main medicinal plants with antioxidant activities in Brazil. Conclusion: Antioxidants are those molecules that are involved in the scavenging of these reactive species causing oxidative stress and are defined as those substances which could prevent the oxidation of the substrate at low concentrations. The main derived exogenous natural antioxidants are derived from medicinal plants, fruits, foods, flowers, and traditional herbal medicines in different parts of the world.

Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4- azatricyclo [5.2.1.0^2,6] dec-8-ene-3,5-dione were designed, synthesized, and their biological activities were evaluated. Methods: The chemical structures of the desired compounds were identified by ¹H NMR, ESI-MS and elementary analysis. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC5079.3μM). Although compound 5 had no effects on endothelial proliferation (IC50=65.3μM), it significantly abrogated endothelial cell migration (IC50=6.7μM). Conclusion: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.

Aims: The rich ethnomedicinal practices of Dakshina Kannada have received considerable attention, and many treatment methods have been documented. This work aimed to explore the traditional medicinal plants originating from Dakshina Kannada for their anti-SARS-CoV-2 activity by employing in silico methodologies. Methods: Virtual screening of Dakshina Kannada's plants was conducted, which are known for their antiviral activities. Potent plants were shortlisted as Tinospora cordifolia, Nyctanthes arbortristis, Bacopa monnieri, Bombax ceiba, and Curcuma longa based on molecular docking scores. Among these, the active plant Tinospora cordifolia possessed the most potent phytochemicals. Molecular dynamics (MD) simulation and MM/GBSA calculations have been performed on cordifolioside A, syringin, and cordioside. Results: Initially, the selected plants were docked into the active site of SARS-CoV-2 protein. MD simulations were performed to investigate the various conformations and validate the docking results, revealing that cordifolioside A and syringin were more stable than cordioside. The stability of the phytoconstituents in complex with SARS-CoV-2 protein was steady throughout the 100 ns simulation time. Finally, the binding free energies were calculated using the MM/GBSA method. The pharmacophore model has confirmed the hydrogen bond interactions, and PASS prediction determined their antiviral activities. Conclusion: Thus, the present study identified the most potent plant from Dakshina Kannada against the SARS-CoV-2 virus as Tinospora cordifolia with powerful phytochemicals (cordifolioside A, syringin and cordioside). Furthermore, in vitro and in vivo experiments are needed to provide experimental data to develop anti-SARS-CoV-2 drugs.

Background: Tuberculosis is considered a global health problem; hence, the screening and synthesis of novel tuberculostatic drugs are a necessity. Molecular docking could drastically reduce the time of hit identification; however, initial validation is required to reduce the false-positive results. Objective: Assessment of several searching and scoring algorithms for a custom dataset of hydrazidehydrazone- based tuberculostatics was conducted to obtain a reliable docking protocol for future virtual screening. Methods: Modification in the scoring functions, size of the grid space, and presence of active waters of a GOLD 5.3 docking protocol was conducted. Subsequently, side-chain flexibility and ensemble docking were carried out to assess the role of protein flexibility in the correlation coefficient. In addition, docking simulations with Glide and free binding energy calculations with MM-GBSA were implemented. The Pearson correlation coefficient between the experimental and the acquired in silico data was calculated after each work step. The major interactions between the top-scored ligands and the active site of 2X22 were visualized applying Discovery Studio. Results: An optimized GOLD 5.3 docking protocol led to a drastically enhanced Pearson correlation coefficient of the training set, from 0.461 to 0.823, as well as an excellent pairwise correlation coefficient in the test set - 0,8405. Interestingly, the Glide docking scores and the free binding energy calculations with MM-GBSA did not achieve reliable results. During the visualization of the top-ranked compounds, it was observed that Lys165 played a major role in the formation of stable complexes. Conclusion: It could be concluded that the performance of the optimized GOLD 5.3 docking protocol demonstrated significantly higher reliability against the hydrazide-hydrazone dataset when compared to Glide docking simulations and MM-GBSA free binding energy calculations. The results could be utilized for future virtual screenings.

Background: Indole and its derivatives play an important role in the synthesis of commercially relevant intermediate molecules required for the synthesis of a wide range of bioactive molecules. Aim: Exploration of the synthesis of novel nonsteroidal anti-inflammatory drugs, as well as their computational studies and pharmacological effects, was aimed as an important component of the present research. Objective: The objective of the present work was to synthesize some novel 1-(1H-indol-1-yl)ethanone compounds, analyze their computational effects on the COX-2 enzyme and test their in vivo analgesic and anti-inflammatory activity. Methods: The condensation of 4-(2-(1H-indol-1-yl)-2-oxoethoxy) benzaldehyde with substituted aniline in ethanol in the presence of a catalytic quantity of glacial acetic acid was performed, which yielded the new Indole derivatives. IR, NMR, mass spectroscopy and elemental analysis techniques were used to characterize the structures of new indole derivatives. To estimate the drug-like candidate’s nature, a number of molecular attributes of these derivatives were computed. The synthesized derivatives were docked with a specific reference cyclooxygenase-2 (COX-2) enzyme. The physical similarity of the newly synthesized derivatives (D1-D8) and indomethacin (the reference drug) was determined by evaluating seven physicochemical features by a software. Results: Although the bioavailability/drug likeness was found to be in the standard range, the synthesized compounds exhibited close similarity with those of the reference drug, and subsequent optimization was necessary. Conclusion: The newly synthesized indole derivatives as COX-2 inhibitors were evaluated for their biological properties, which included anti-inflammatory and analgesic efficacy. Other: D-7 (1-(1H-indol-1-yl)-2-(4-((4-nitrophenyl)imino)methyl)phenoxy)ethanone) was found to have the strongest anti-inflammatory and analgesic activity amongst the eight target compounds.

Background: Peritoneal adhesions (PA) are a common complication of abdominal operations. Previous studies indicate that inhibition of inflammation and fibrosis at sites of peritoneal damage may prevent the development of intra-abdominal adhesions. Zingiber officinalis Roscoe (ginger) and Panax ginseng (P. ginseng) are herbal products with antioxidant and anti-inflammatory effects that can have restorative properties. Objective: This research aimed to examine the impact of ginger and P. ginseng on prevention of PA in a rat model after surgery. Methods: Following a laparotomy, the wall of the cecum was rubbed to induce intra-abdominal adherence in Wistar rats. Ginger (400mg/kg) and P. ginseng (500mg/kg) were orally adminstered to the animals. The animals were sacrificed on the 10th day after surgery, and the Nair and Leach scoring system was used to assess adhesion. The microscopic histology of the induced cecal adhesions was evaluated. An enzyme-linked immunosorbent assay (ELISA) was used to determined tissue levels of transforming growth factor-beta (TGF-β) on homogenized PA tissue. Real-time PCR was performed to quantify the mRNA expression of IL-1β, TNF-α, Col 1a1, and Col 3a1 in rat tissue. Results: The adhesion score and histopathological rating based on the Nair and Leach scoring criteria showed lower adhesion scores in the group of rats treated with P. ginseng compared to the control group (p<0.05). Treatment with ginger and P. ginseng was associated with reduced tissue level of TGF-β and mRNA expression of TNF-α and IL-1β. The gene expression level of Col 1a1 and Col 3a1 were markedly decreased in the P. ginseng group. Conclusion: The study's outcome recommends that P. ginseng could be an effective agent for preventing the PA and inflammation during the post-operative stage.

Aims: This study documented hepatic tissue's protective activity against oxidative damage mediated experimental models of breast cancer. Background: Gaviola has a long history of improving the protection mechanism against many diseases as an antioxidant and anticancer dietary agent. Objective: The purpose of this study is to establish changes in hepatic profiling, antioxidants, inflammatory cytokine expression, and DMBA-induced hepatic histopathology of mammalian rats. Methods: 7,12-dimethylbenz[a] anthracene (DMBA), PAHs, used orally in female Sprague Dawley rats Fifty-seven days-old with breast cancer single-dose diluted in sesame oil of 20 mg/kg/body weight. The cancer-bearing animals had 45 days gastrogavagated at 200 mg/kg/body weight with Graviola. The serum samples were taken at the end of the experiment. The rats were sacrificed to establish the hepatic protective activity of the Graviola by testing hepatic and oxidative stress markers. Results: Graviola therapy shows that enzymatic and non-enzymatic antioxidants and lipid peroxide levels have increased efficiency and have restored the high activity of hepatic marker enzymes such as ALT, AST, ALP, and GGT. To date, hepatic expression of nuclear factor erythroid 2-like 2 (Nfe2l2) and nuclear factor kappa B subunit 1 (Nfkb1) mediated rats have normalized. In addition, histological observations have demonstrated that Graviola's treatment effectively protects the liver from the oxidative damage caused by DMBA, reinforcing its hepatic defensive nature. Conclusion: Graviola therapy improves the efficiency of both enzymatic and non-enzymatic antioxidants and lipid peroxide levels. It also helps in the restoration of other liver enzymes.

Purpose: To investigate the underlying mechanism of cardiomyocyte protection of carvedilol based on autophagy and apoptosis. Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to various concentrations of carvedilol before anoxia, and pretreated with 3-MA or compound C for inhibiting autophagy or p-AMPK expression. CCK-8 colorimeter and flow cytometry were used to determine the cell viability and apoptotic rates. The variation of mRNA and protein was measured by RT-PCR and Western blot. The presence of autophagosomes was observed by electron microscopy. Results: First, we found that carvedilol increased autophagic marker levels in a concentration-dependent manner and the number of autophagosomes in NRVMs. Moreover, carvedilol substantially enhanced the viability and noticeably reduced the CK, MDA and LDH levels and cell apoptosis rate compared with the anoxia group. In addition, carvedilol decreased the levels of caspase-3 and Bim in mRNA and protein, but such effect was blocked by the special autophagy inhibitor-3-MA, and the number of autophagosomes was significantly decreased when treated with 3-MA, indicating that carvedilol exhibited anti-apoptotic and anti-injury effects by inducing autophagy in anoxia NRVMs, but these effects can be abolished by adding 3-MA to suppress autophagy. Finally, the carvedilol treatment-induced autophagy by enhancing the activation of p-AMPK and inhibiting p-mTOR. Electron microscopy presented that the number of autophagosomes was significantly decreased when treating with compound C, indicating that carvedilol induced autophagy in anoxia NRVMs partly by the AMPK-mTOR signaling pathway. Conclusion: Carvedilol has cardioprotection by inducing autophagy against apoptosis partly through the AMPK/mTOR pathway during anoxia in NRVMs.

Background: Cancer is a complex disease in which some of the cells grow uncontrollably and spread to other parts of the body. Objective: The present study focuses on molecular docking and synthesis of novel flavone derivatives substituted with heterocyclic rings. Methods: The anticancer activity of novel flavones against human aromatase enzyme using human breast cancer cell line MCF-7 through MTT assay was demonstrated. The synthesized compounds for the determination of single or double-strand DNA damage through the single-cell electrophoresis/comet assay were evaluated. Results: In this study, we found that the derivative 3M with morpholine ring showed the highest anticancer potency against the MCF-7 cell line compared to that of other flavone derivatives. Compound 3T showed less cytotoxicity against the MCF-7 cell line. Conclusion: Based on the findings, flavone scaffolds can be selected as a skeleton for the development of heterocyclic amine-containing flavones with the potential to develop as anticancer drugs.

Background: The heterocyclic nucleus pyrimidine is present in several natural and synthetic chemical analogues and has proved its broad medicinal applications. Further, pyrimidine in the form of parent structure or basic skeleton of RNA and DNA is involved in controlling the immune functioning, and in turn, inflammatory reactions. Objective: The objective of the present study is to evaluate some novel pyrimidine analogues for antiinflammatory action. Methods: Molecular docking studies of Indomethacin and selected analogues were carried out with the COX-2 enzyme (PDB: 4ZOL). The synthesis of derivatives of 4-Phenyl-6-(phenylamino)pyrimidine-2-ol derivatives was begun by following Perkin condensation between substituted acetanilides and substituted aromatic aldehydes to yield an intermediate, which in turn produces the required nucleus for treatment with urea. All synthesized compounds were evaluated for in vivo and in vitro anti-inflammatory activity. Results: The docking interaction reflects a good dock score when compared with indomethacin, a potent Anti-inflammatory drug. In the majority of the compounds, pyrimidine was able to form hydrogen bonding while the rest of the part was involved in hydrophobic bonding. All compounds were synthesized in good yield and confirmed by physical and spectral studies. In vitro studies showed that compounds 5a and 5e were better at controlling inflammation than the conventional treatment Antipyrine, while in vivo data showed that compounds 5a, 5c, 5e, and 5h were better at controlling inflammation than the standard drug Antipyrine. Conclusion: The compound with more than one electron releasing group on the aniline moiety of pyrimidine yields a decent result in the synthetic and experimental studies, but the absence of an electron withdrawing group favours stronger anti-inflammatory activity on the target.

Aim: Several new dihydropyridine-based calcium channel blockers have been synthesized and pharmacologically evaluated for the treatment of hypertension Background: Dihydropyridines constitute an important class of calcium channel blockers (CCBs) due to their high potency, wide heterogeneity and tremendous biological usefulness. As a follow-up to our previous studies on 4-aryl-1,4-dihydropyridines as calcium channel blockers for the treatment of hypertension, four new series of methyl ethyl ester substituted 1,4-dihydropyridines are reported. Objectives: The aim of the work was to study the effects of unsymmetrical ester substitutions on calcium channel blocking activity of dihydropyridines (DHPs) while retaining the aminoalkoxy side chain at various positions of the 4-aryl ring. The type and location of the substituents on the 4-aryl ring have been extensively explored to study the structure-activity relationship (SAR) in this series of dihydropyridines as calcium channel blockers. Methodology: The target DHPs were synthesized using modified Hantzsch condensation and further derivatization. The compounds were screened for their inhibitory potential against L-type calcium channels at a single concentration of 10 μM on NG108-15 cells (Neuroblastoma X Glioma). The most potent DHP 12 was also tested for its vasodilatory activity using rat thoracic aortic rings precontracted with KCl (30 mM) and in vivo antihypertensive activity in rats using the tail-cuff method. Results: The newly synthesized DHPs displayed diversified calcium channel blocking activity with compounds 1e, 1h, 2d, 2f, 2h, 6, 9, 11, 12 and 14, producing more than 50% inhibition of veratridine response. 3-imidazolylpropoxy substituted analogue 12 turned out to be the most potent compound of the four series of compounds and produced fairly higher inhibition (78.6%) of veratridine response in comparison to nifedipine (70%) at 10 μM. In addition, compound 12 produced potent vasodilatory and antihypertensive properties. Conclusion: Both location of the side chain and the type of substituent on methyl ethyl ester substituted 4-aryl ring affected the response of dihydropyridine derivatives towards L-type calcium channels.

Background: In the current Alzheimer’s disease therapy as the preferred treatment are applied acetylcholinesterase inhibitors. Aiming to identify the active pharmacophores necessary for increased acetylcholinesterase inhibitory activity, some docking studies have been applied. Methods: In silico docking evaluation of the binding modes, identification of acetylcholinesterase inhibitory activity in vitro through Ellman’s test and ITC protocol, and the in vivo effect. PAMPA evaluation of the GIT and BBB permeability. Results: In the present study, two series previously synthesized in our laboratory, arylpiperazine derivatives of theobromine, were docked into the rhAChE active sites. Ellman’s test outlined molecules LA1 and LA7 as the most active, with IC50 of 0.708 and 0.299 μM, respectively. In the acute toxicity test, LA7 given intraperitoneally in mice showed moderate toxicity with LD50 of 87.5 mg/kg. The new compound, administered i.p. for 12 days at doses 2 mg/kg/day and 4 mg/kg/day, respectively, showed a pronounced acetylcholinesterase inhibitory activity in vivo. Conclusion: The corresponding binding modes were identified, where the docking pose for the studied molecules depends on the protonated state of the nitrogen atom of the piperazine moiety. In the best scored pose for LA7, the xanthine moiety is bound into the catalytic active site (CAS) of acetylcholinesterase, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). For the evaluated selected structures, good permeability through the GIT and BBB assessed by PAMPA was also determined.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a positive- sense, single stranded RNA virus, responsible for the pandemic outbreak called COVID-19. The pandemic, still ongoing, had presented unprecedented challenges in terms of finding appropriate pharmacological treatments. Methods: Starting from the recent literature that demonstrates how ALKBH5 inhibitors could be used as a new strategy to reduce SARS-CoV-2 replication, we decided to repurpose our newly discovered ALKBH5 inhibitor MV1035, previously tested and proved effective against glioblastoma, for its putative antiviral activity against SARS-CoV-2. We demonstrated a reduction in SARS-CoV- 2-induced CPE after 72 h incubation using MV1035 (50 μM), for SARS-CoV-2 wild type (Wuhan strain) and South African variant. Results: The results show how MV1035 seems to be able to reduce SARS-CoV-2 replication through an indirect mechanism of action, which might involve an interaction with the host cell rather than with a virus protein. Conclusion: This may be particularly interesting as it lays the foundation for the rational design of molecules in principle not subject to drug resistance, as host cell proteins are not affected by virus mutations.

Background: Pyrimidine and 1,2,4-triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericides, fungicides, vermicides, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: A novel set of heterocyclic derivatives comprising 1,2,4-triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity. Methods: In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl-pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti-TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain. Results: Our results revealed that the target 1,2,4-triazoles 7d, 7e, 7c have potent potency against Gram- (+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 μg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram-(-ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 μg/mL). Among all tested compounds, 7a, 7e, and 7h revealed an outstanding antitubercular activity against M. tuberculosis H37Rv strain with MICs of 3.24, 8.93, and 4.70 μg/mL, respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 ŝ, LysA:103 [3.103, 2.164 ŝ, GlyA:102 [1.713 ŝ, ArgA:238 [1.713 ŝ, ValA:101 [2.113 ŝ (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 ŝ [Pi-Pi], respectively. Conclusion: In this communication, our aim has been verified by the synthesis of 3-methoxy-10,12- dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4-triazole and pyrimidine moieties with benzoxepine in a single molecular framework were found. After all the above findings, it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.