在本文中，我们继续之前的努力，基于EGFR和VEGFR-2抑制剂的基本药效学要求，开发新的选择性抗癌候选药物。因此，设计并测试了二十二个新的4-噻吩基-吡唑、吡啶和嘧啶衍生物，作为双重EGFR/VEGFR-2抑制剂。此外，前面报道的核苷类化合物具有抗微生物活性，这促使我们对它们进行抗细菌和抗真菌作用的筛选。首先，评估新合成的衍生物对HepG-2和MCF-7两种癌细胞系的抗肿瘤活性。值得注意的是，化合物2a、6a、7a、10b、15a和18a对HepG-2和MCF-7 两种癌细胞系表现出卓越的抗癌活性，被选为进一步评估其抗EGFR和抗VEGFR-2潜力的候选药物，并发现与erlotinib和sorafenib相比，它们的潜力非常有希望。化合物10b和2a均具有更好的双重EGFR/VEGFR-2抑制能力，IC50值分别为0.161和0.141μM以及0.209和0.195μM。此外，选择最活跃的10b来评估细胞周期阻滞的确切阶段，并调查癌细胞死亡的确切机制，无论是由于凋亡还是坏死。另一方面，测试了所有合成的化合物对革兰氏阳性菌，如金黄色葡萄球菌和枯草杆菌以及革兰氏阴性菌，如大肠杆菌和铜绿假单胞菌的抗菌活性。此外，还研究了对白色念珠菌和黄曲霉菌株的抗真菌活性。抗微生物试验的结果显示，大多数化合物表现出强到中度的抗菌和抗真菌效应。为了了解这些化合物与活性位点结合的模式，所有新合成的候选化合物都被引入EGFR和VEGFR-2结合位点进行了两种不同的对接过程。此外，我们还尝试通过DFT计算将化合物10b和参考药物（erlotinib和sorafenib）进行关联。最后，根据这些新的吡唑、吡啶和嘧啶衍生物作为抗癌和抗微生物候选药物的生物数据，我们得出了非常有趣的SAR以供进一步优化。本期刊为©皇家化学学会所有。

In this article, we continued our previous effort to develop new selective anticancer candidates based on the basic pharmacophoric requirements of both EGFR and VEGFR-2 inhibitors. Therefore, twenty-two novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives were designed and examined as dual EGFR/VEGFR-2 inhibitors. Besides, the previously reported antimicrobial activities of the aforementioned nuclei motivated us to screen their antibacterial and antifungal activities as well. First, the antitumor activities of the newly synthesized derivatives were evaluated against two cancer cell lines (HepG-2 and MCF-7). Notably, compounds 2a, 6a, 7a, 10b, 15a, and 18a exhibited superior anticancer activities against both HepG-2 and MCF-7 cancer cell lines. These candidates were selected to further evaluate their anti-EGFR and anti-VEGFR-2 potentialities which were found to be very promising compared to erlotinib and sorafenib, respectively. Both 10b and 2a derivatives achieved better dual EGFR/VEGFR-2 inhibition with IC50 values of 0.161 and 0.141 μM and 0.209 and 0.195 μM, respectively. Moreover, the most active 10b was selected to evaluate the exact phase of cell cycle arrest and to investigate the exact mechanism of cancer cell death whether it be due to apoptosis or necrosis. On the other hand, all the synthesized compounds were tested against Gram-positive bacteria such as S. aureus and B. subtilis as well as Gram-negative bacteria such as E. coli and P. aeuroginosa. Also, the antifungal activity was investigated against C. albicans and A. flavus strains. The findings of the antimicrobial tests revealed that most of the investigated compounds exhibited strong to moderate antibacterial and antifungal effects. Furthermore, to understand the pattern by which the investigated compounds bound to the active site, all the newly synthesized candidates were subjected to two different docking processes into the EGFR and VEGFR-2 binding sites. Besides, we tried to correlate compound 10b and the reference drugs (erlotinib and sorafenib) through DFT calculations. Finally, following the biological data of the new pyrazole, pyridine, and pyrimidine derivatives as anticancer and antimicrobial candidates, we concluded a very interesting SAR for further optimization.This journal is © The Royal Society of Chemistry.