RESUMEN
RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.
Asunto(s)
Lesión Pulmonar Aguda , Bencenosulfonamidas , Sulfonamidas , Canales Catiónicos TRPV , Relación Estructura-Actividad , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Animales , Ratones , Humanos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones Endogámicos C57BLRESUMEN
Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, including Mycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed by M. smegmatis against COG1410 involving ClpC. Upon subjecting M. smegmatis to serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance.
RESUMEN
The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.
Asunto(s)
Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Animales , Ratones , Antivirales/farmacología , ZidovudinaRESUMEN
Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 µmol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2-10 °C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high water-solubility and short plasma half-life into attractive nanomedicines.
Asunto(s)
Gemcitabina , Neoplasias Pancreáticas , Humanos , Liposomas/uso terapéutico , Desoxicitidina/uso terapéutico , Desoxicitidina/farmacología , Línea Celular Tumoral , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Lípidos/uso terapéuticoRESUMEN
The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5'-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5'-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC50 value of 8.78 µM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/ß receptor-deficient (Ifnar-/-) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5'-amino NI structure skeleton for developing antiviral NIs.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Ratones , Virus Zika/fisiología , Infección por el Virus Zika/tratamiento farmacológico , Antivirales/química , Ratones Endogámicos ICR , Replicación ViralRESUMEN
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H37Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Animales , Ratones , Antituberculosos/toxicidad , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Descubrimiento de Drogas , Pruebas de Sensibilidad Microbiana , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.
Asunto(s)
Antivirales , Benzoxazoles , Subtipo H1N1 del Virus de la Influenza A , Piperazinas , Tetrazoles , Benzoxazoles/química , Benzoxazoles/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Piperazinas/química , Piperazinas/farmacología , Tetrazoles/química , Tetrazoles/farmacología , Relación Estructura-Actividad , Antivirales/química , Antivirales/farmacología , HumanosRESUMEN
RG7834, a dihydroquinolizinone (DHQ) candidate developed by Roche Pharma, was expected to realize the "functional cure of HBV". However, it was dismissed in phase I clinical trial due to its neurotoxicity. In this study, a series of new DHQ derivatives containing a cyclic ether or benzo-fused (cyclic) ether moiety were designed, synthesized and evaluated for their in vitro activity. Many of them exhibited potent inhibition activity against HBsAg, HBeAg and HBV DNA. More importantly, in the in vitro neurotoxicity evaluation, most of the PC12 cells treated with RG7834 became round and even shrunken with the disappearance of neurites; in contrast, most of the cells treated by (2'S, 6S)-1a, showed similar morphological structures to the control group with clearly visible neurites, indicating that (2'S, 6S)-1a could have improved neurotoxicity. The first study of the structure-neurotoxicity relationship of DHQs paves the way for the future development of DHQs.
Asunto(s)
Antivirales , Virus de la Hepatitis B , Antivirales/química , Antivirales/farmacología , ADN Viral , Éteres Cíclicos , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis BRESUMEN
5-Fluorouracil (5-FU) is a chemotherapeutic drug against many types of cancers, especially colorectal cancer. However, its short plasma half-life and serious adverse reactions limit its wide clinical applications. To overcome these shortcomings, a novel lipophilic 5-FU carbonate [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl tetradecyl carbonate] was designed, synthesized, and encapsulated into liposome (LipoXL-01) by a thin-film dispersion method through formulation screening and optimization. LipoXL-01 was characterized by a particle size of around 100 nm, polydispersity index of 0.200, ζ-potential value of -41 mV, encapsulation efficiency of 93.9%, and drug-loading efficiency of 11.6%. The cellular uptake of LipoXL-01 was increased in a concentration-dependent manner on HCT15 cells. LipoXL-01 could enhance the induction of cell apoptosis and the inhibition of cell migration and arrest the ability of the cell cycle at the S-phase on HCT15 cells better than 5-FU. Additionally, LipoXL-01 exhibited a slow drug release profile with a cumulative release rate of 12% in 8 h. The results of pharmacokinetic and biodistribution studies revealed that LipoXL-01 had a long plasma half-life (7.21 h) and a high tumor accumulation (733 nmol/g at 8 h). The in vivo antitumor effect study also showed that LipoXL-01 had more potent efficacy than 5-FU (65 vs 48% of the tumor-inhibition rate). Simultaneously, negligible systemic toxicity was observed via analyzing the body weight as well as hematological and pathological parameters in the tested mice. The current study suggested that LipoXL-01 might be a promising nanocandidate for chemotherapy of colorectal cancer.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carbonatos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Fluorouracilo/uso terapéutico , Liposomas/uso terapéutico , Ratones , Distribución TisularRESUMEN
Three series of novel nitrofuran-1,3,4-oxadiazole hybrids were designed and synthesized as new anti-TB agents. The structure activity relationship study indicated that the linkers and the substituents on the oxadiazole moiety greatly influence the activity, and the substituted benzenes are more favoured than the cycloalkyl or heterocyclic groups. Besides, the optimal compound in series 2 was active against both MTB H37Rv strain and MDR-MTB 16883 clinical isolate and also displayed low cytotoxicity, low inhibition of hERG and good oral PK, indicating its promising potential to be a lead for further structural modifications.
Asunto(s)
Antituberculosos/farmacología , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Nitrofuranos/farmacología , Oxadiazoles/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nitrofuranos/química , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
GYH2-18 is a type II HBV CAM with 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamine (DPPC) skeleton discovered by Roche INC. A series of GYH2-18 derivatives were designed, synthesized and evaluated for their anti-HBV activity. Two compounds 2f and 3k exhibited excellent anti-HBV activity, low cytotoxicity and accepted oral PK profiles. Chiral separation of 2f and 3k was conducted successfully, and (6S)-cyclopropyl DPPC isomers 2f-1, 2f-3, 3k-1 and 3k-3 were identified to be much more active than the corresponding (6R)-ones. The preliminary structure-activity relationship, particle gel assay and molecular modeling studies were also discussed, which provide useful indications for guiding the further rational design of new (6S)-cyclopropyl DPPC analogues.
Asunto(s)
Antivirales/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Pirazinas/farmacología , Antivirales/síntesis química , Antivirales/química , Proteínas de la Cápside/metabolismo , Relación Dosis-Respuesta a Droga , Virus de la Hepatitis B/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral administration. In this study, we reported the modification and structure-activity relationship (SAR) of C (piperazine ring) and E (phenyl ring) rings of JNJ4796. Compound (R)-2c was identified to show excellent in vitro activity against IAV H1N1 and Oseltamivir-resistant IAV H1N1 stains (IC50: 0.03-0.06 µM), low cytotoxicity (CC50 > 200 µM), accepted oral PK profiles and low inhibition rate of hERG (13.2%, at 10 µM). Evaluation for the in vivo anti-IAV efficacy of (R)-2c will begin soon.
Asunto(s)
Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Piperazina/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Tetrazoles/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperazina/síntesis química , Piperazina/química , Piperazinas/síntesis química , Piperazinas/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/químicaRESUMEN
A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016 µg/mL), and good safety index (CC50: >64 µg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery.
Asunto(s)
Antibacterianos/farmacología , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Piperazina/farmacología , Tiazinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperazina/química , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/químicaRESUMEN
A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 µM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.
Asunto(s)
Antibacterianos/farmacología , Diseño de Fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin/análogos & derivados , Rifampin/farmacología , Tiazinas/farmacología , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Rifampin/administración & dosificación , Rifampin/química , Relación Estructura-Actividad , Tiazinas/administración & dosificación , Tiazinas/química , Células VeroRESUMEN
A series of new benzothiazinone derivatives containing a symmetric 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, based on the structure of LK02 discovered in our lab, were designed and synthesized. With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016 µg/mL). Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169.
Asunto(s)
Alcanos/química , Antituberculosos/química , Diseño de Fármacos , Tiazinas/química , Animales , Antituberculosos/síntesis química , Resistencia a Medicamentos , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.
Asunto(s)
Aminoácidos/química , Aminoácidos/metabolismo , Benzamidas/química , Virus de la Hepatitis B/efectos de los fármacos , Piperidinas/química , Profármacos , Antivirales , Diseño de Fármacos , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacologíaRESUMEN
A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037⯵g/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oximas/farmacología , Tiazinas/farmacología , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Diseño de Fármacos , Femenino , Humanos , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Oximas/química , Oximas/farmacocinética , Piperazinas , Tiazinas/química , Tiazinas/farmacocinética , Tuberculosis/tratamiento farmacológicoRESUMEN
A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 µM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 µM), a bis(l-valine) ester prodrug of TFV, was found to have obviously greater AUC0-∞, C max, and F% than tenofovir disoproxil fumarate (TDF), and potent in vivo efficacy which is not inferior to TDF in a duck HBV (DHBV) model and a HBV DNA hydrodynamic mouse model, and it may serve as a promising lead compound for further anti-HBV drug discovery.
RESUMEN
IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IRâ¯>â¯90% at 10⯵M). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078⯵M), and had lower hERG binding affinity (IRâ¯<â¯50% at 10⯵M). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.
Asunto(s)
Antituberculosos/farmacología , Benzotiazoles/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/síntesis química , Antituberculosos/química , Benzotiazoles/síntesis química , Benzotiazoles/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.